Compounds for the treatment of proliferative disorders

ABSTRACT

The invention relates to compounds of structural formula (I):  
                 
         or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, wherein R a , R b , and R 2  are defined herein. These compounds inhibit tubulin polymerization and/or target vasculature and are useful for treating proliferative disorders, such as cancer.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/738,340 filed Nov. 18, 2005, the entire teachings of which areincorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namelyisothiazole derivatives that may be used for treating or preventingproliferative disorders.

BACKGROUND OF THE INVENTION

Many chemotherapeutic methods are now available to be used in thetreatment of cancer. One of the most successful methods is the use ofanti-mitotic agents which interfere with the assembly or disassembly ofmicrotubules. Since microtubule assemble and disassemble is necessaryfor mitosis, inhibition of either the assembly or disassembly ofmicrotubules interferes with cell proliferation. Thus, compounds thatinhibit the assembly of microtubule are useful in treating diseases orconditions which are caused or exasperated by rapid or abnormal cellproliferation, such as cancer.

Several anti-mitotic agents have had considerable clinical success. Forexample, the following vinca alkaloids which inhibit microtubuleassembly have proved clinically successful: Vincristine has beensuccessfully used to treat hematological malignancies and non-small-celllung carcinoma; Vinblastine has been successfully used to treathematological malignancies, testicular carcinomas and non-small-celllung carcinoma; and Vinorelbine has been successfully used to treathematological malignancies, breast carcinomas and non-small-cell lungcarcinoma. In addition, taxanes which inhibit microtubule disassemblehave also proved to be clinically successful. For example, Paclitaxelhas been successful in treating breast, ovarianand non-small-cell lungcarcinomas; and Docetaxel has been successful in treating breast andnon-small-cell lung carcinomas.

Despite these successes, available anti-mitotic agents are inadequatefor a number of reasons. For example, paclitaxel, docetaxel andvincristine are associated with significant neuropathy which can limittheir use in repeat courses of therapy. In addition, both the vincaalkaloids and taxanes are good substrates for the 170 kDa P-glycoprotein(Pgp) efflux pump found in most multi-drug resistant cells. This proteinpumps a drug out of the tumor cells causing the tumor cells to becomeresistant to treatment. Once a patient's cancer has become multi-drugresistant, there is typically little that can be done to halt or retardfurther progression of the disease.

There is therefore still a need for new drugs which overcome one or moreof the aforementioned shortcomings of drugs currently used in thetreatment of cancer. Desirable properties of new anti-cancer drugstherefore include a good therapeutic index, efficacy against tumors thatare currently untreatable or poorly treatable, efficacy againstmulti-drug resistant tumors and/or reduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certainisothiazole derivatives that inhibit tubulin polymerization. Compoundsof the invention are also capable of vascular targeting, in particular,blocking, occluding, or otherwise disrupting blood flow inneovasculature. These compounds are particularly useful for treating orpreventing proliferative disorders, such as cancer.

In one embodiment, the invention relates to compounds of formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl or an optionally substituted heteroaryl; and    -   R₂ is an optionally substituted aryl or an optionally        substituted heteroaryl, provided that R₂ is not an unsubstituted        phenyl.

In another embodiment, the invention relates to compounds of formula(IA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl, or an optionally substituted heteroaryl; and    -   R^(x) is (R^(aa))_(m), —R_(aa)—C(O)(CH₂)_(n)C(O)OH,        —C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or        —(R^(aa))_(q)C(O)(Y₁);    -   R^(y) is —H or lower alkyl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, or an optionally substituted        heteraralkyl;    -   R^(aa) is an amino acid residue or an amino acid residue analog;    -   Y is CH₂, O, or NH;    -   R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁;    -   Alk is an optionally substituted alkylene;    -   Het is an optionally substituted heteroalkyl;    -   Y₁ is a water soluble polymer with a molecular weight less than        60,000 daltons;    -   n is 1, 2, 3, or 4;    -   m is an integer from 1 to 10; and    -   q is 0 or 1.

In another embodiment, the invention relates to compounds of formula(IB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, or an optionally substituted        heteraralkyl;    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl or an optionally substituted heteroaryl.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are potent antimitotic agentswhich inhibiting tubulin polymerization, and thus can inhibitmicrotubule growth. In order for cells to undergo mitosis, microtubulesmust be able to assemble and disassemble, in a process known as dynamicinstability. Thus, in one embodiment, the compounds of the invention canbe used to inhibit tubulin polymerization in a cell by contacting thecell with an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to inhibittubulin polymerization in a subject by administering to the subject aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are vascular targeting agentswhich can be used to block, occlude, or otherwise disrupt blood flow inneovasculature, and thus lead to destruction of vasculature. Thus in oneembodiment, compounds of the invention can be used to block, occlude, orotherwise disrupt blood flow in neovasculature by contacting theneovasculature with an effective amount of a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to block,occlude, or otherwise disruptblood flow in neovasculature of a subjectby administering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

Since the compounds of the invention disrupt mitosis by inhibitingtubulin polymerization, they are particularly useful in treating orpreventing proliferative disorders, such as cancer. Therefore, in oneembodiment, compounds of the invention or pharmaceutically acceptablesalts, solvates, clathrates, or prodrugs thereof can be used to treat orprevent a proliferative disorder in a subject by administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otheranti-cancer agents.

As will be described in detail below, compounds of the inventionovercome or ameliorate some of the limitations of known anti-mitoticagents. In particular, compounds of the invention are cytotoxic inmultidrug resistant cells, and thus may be useful for treating cancersthat have become resistant to other therapies.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term an “aromatic ring” or “aryl” means a monocyclicor polycyclic-aromatic ring or ring radical comprising carbon andhydrogen atoms. Typically, aryl groups have about 6 to about 14 carbonatom ring members. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano,halo, amino, and nitro. In certain embodiments, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR³², wherein R³² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be optionally substituted with one or more substituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be optionallysubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Alkoxy groups can beoptionally substituted with one or more substituents.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Alkylsulfanylgroups can be optionally substituted with one or more substituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom. Arylsulfanylgroups can be optionally substituted with one or more substituents.

The term “alkyl ester” as used herein, refers to a group represented bythe formula —C(O)OR₃₂, wherein R₃₂ is an alkyl group. A lower alkylester is a group represented by the formula —C(O)OR₃₂, wherein R₃₂ is alower alkyl group.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₃₃—, wherein R₃₃ is H or a lower alkyl. Heteroalkyl groups can beoptionally substituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be optionally substitutedwith one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbonon radical typically having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groupscan be optionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be optionally substituted with one or moresubstituents.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be optionallysubstituted with one or more substituents.

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic or polycyclic heterocyclic ring (typically having 3- to14-members) which is either a saturated ring or an unsaturatednon-aromatic ring. A 3-membered heterocycle can contain from 1 to 3heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 toabout 8 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The heterocycle may be attached via anyheteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents (including without limitation a halo, an alkyl, ahaloalkyl, or aryl). Only stable isomers of such substitutedheterocyclic groups are contemplated in this definition.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in which atleast 1 ring member is a heteroatom selected from oxygen, sulfur andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment, the heteroaromatic ring system has a 7 to 14 ring membersand may contain from 1 to about 7 heteroatoms. Representativeheteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl,benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl,tetrazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl orbenzo(b)thienyl and the like. Heteroaryl groups may be optionallysubstituted with one or more substituents

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted [1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moeity, the identity of thesubstitutent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, adialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, ahaloalkyl, —C(O)NR₃₄R₃₅, —NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro,haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅, —SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆,—NR₃₆C(O)NR₃₄R₃₅, —OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —S(O)_(p)R₃₆, or—S(O)_(p)NR₃₄R₃₅, wherein R₃₄ and R₃₅, for each occurrence are,independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or aheteraralkyl; or R₃₄ and R₃₅ taken together with the nitrogen to whichthey are attached is a heterocyclyl or a heteroaryl; and R₃₆ and R₃₇ foreach occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl,a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl;

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one ore more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I), (V) through (X),(IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofand also include protected derivatives thereof.

As used herein, the term “amino acid residue” refers to what is left ofan amino acid (losing a H⁺ from the nitrogenous side, an OH⁻ from thecarboxylic side, or a H⁺ from the nitrogenous side and an OH⁻ from thecarboxylic side) in the formation of a peptide bond(s). An “amino acidanalog” includes D or L amino acids having the following formula:NH₂—CHR—C(O)OH, wherein R is an optionally substituted alkyl group, anoptionally substituted heteroalkyl group, an optionally substitutedaromatic group, or an optionally substituted heteroaromatic group, andwherein R does not correspond to the side chain of a naturally-occurringamino acid. An “amino acid residue analog” refers to what is left of anamino acid analog (losing a H⁺ from the nitrogenous side, an OH⁻ fromthe carboxylic side, or a H⁺ from the nitrogenous side and an OH⁻ fromthe carboxylic side) in the formation of a peptide bond(s).

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I), (V) through (X), (IA), (VA)through (XA), (IB), (VB) through (XB), or Table 1 that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of compounds of any one offormulas (I), (V) through (X), (IA), (VA) through (XA), (IB), (VB)through (XB), or Table 1 that comprise —NO, —NO₂, —ONO, or —ONO₂moieties. Prodrugs can typically be prepared using well-known methods,such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUGDISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5^(th) ed), theentire teachings of which are incorporated herein by reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I), (V) through (X), (IA), (VA) through (XA), (IB), (VB)through (XB), or Table 1. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I), (V) through (X), (IA), (VA) through(XA), (IB), (VB) through (XB), or Table 1 having an acidic functionalgroup, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I), (V) through (X),(IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1 having abasic functional group, such as an amino functional group, and apharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude, but are not limited to, hydrogen sulfate, citric acid, aceticacid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide,nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylicacid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid,formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I), (V)through (X), (IA), (VA) through (XA), (IB), (VB) through (XB), orTable 1. The term solvate includes hydrates (e.g., hemi-hydrate,mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

Inhibition of tubulin polymerization can be determined by any methodknown to those skilled in the art, such as the method described hereinin Example 4. In addition the amount of a tubulin polymerizationinhibitor that inhibits 50% of tubulin polymerization that occurs in theabsence of the inhibitor (i.e., the IC₅₀) can be determined bypre-incubating purified tubulin with various amounts of an inhibitor for15 minutes at 37° C. The mixture is then cooled to room temperature andGTP is added to induce tubulin polymerization. The polymerization can bemonitored in a spectrophotometer at 350 nm. A typical reaction mixtures(0.25 mL) contains 1.5 mg/mL tubulin, 0.6 mg/mL microtubule-associatedproteins (MAPs), 0.5 mM GTP, 0.5 mM MgCl.sub.2, 4% DMSO and 0.1M4-morpholineethanesulfonate buffer (MES, pH 6.4).

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.,diabetic retinopathy or other retinopathies), choroidalneovascularisation (e.g., macular degeneration), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, and desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated or prevented by the methods of the present inventioninclude, but are not limited to human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by theK562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cellline); myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B. C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

In one embodiment, the compounds of the invention are believed to beparticularly effective in treating subject with hematologicalmalignancies (e.g., Hodgkin's disease, Non-Hodgkin lymphoma, acutelymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic lymphocytic leukemia, and multiple myeloma). Inanother embodiment, the compounds of the invention are believed to beparticularly useful in treating solid tumors.

In one embodiment, the compounds of the invention are particularlyeffective at treating subjects whose cancer has become “multi-drugresistant”. A cancer which initially responded to an anti-cancer drugbecomes resistant to the anti-cancer drug when the anti-cancer drug isno longer effective in treating the subject with the cancer. Forexample, many tumors will initially respond to treatment with ananti-cancer drug by decreasing in size or even going into remission,only to develop resistance to the drug. Drug resistant tumors arecharacterized by a resumption of their growth and/or reappearance afterhaving seemingly gone into remission, despite the administration ofincreased dosages of the anti-cancer drug. Cancers that have developedresistance to two or more anti-cancer drugs are said to be “multi-drugresistant”. For example, it is common for cancers to become resistant tothree or more anti-cancer agents, often five or more anti-cancer agentsand at times ten or more anti-cancer agents.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin vivo or in vitro. In the case of proliferative disorders, abeneficial clinical outcome includes reduction in the extent or severityof the symptoms associated with the disease or disorder and/or anincrease in the longevity and/or quality of life of the subject comparedwith the absence of the treatment. For example, for a subject withcancer, a “beneficial clinical outcome” includes a reduction in tumormass, a reduction in the rate of tumor growth, a reduction inmetastasis, a reduction in the severity of the symptoms associated withthe cancer and/or an increase in the longevity of the subject comparedwith the absence of the treatment. The precise amount of compoundadministered to a subject will depend on the type and severity of thedisease or condition and on the characteristics of the subject, such asgeneral health, age, sex, body weight and tolerance to drugs. It willalso depend on the degree, severity and type of proliferative disorder.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. Effective amounts of the disclosedcompounds typically range between about 1 mg/mm² per day and about 10grams/mm² per day, and preferably between 10 mg/mm² per day and about 1gram/mm².

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forblocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; pulmonary edema;asthma; nasal polyps; inflammatory bowel disease; periodontal disease;ascites; peritoneal adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation; angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis.

Vascular targeting can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Examples 7and 8.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I), (V) through (X), (IA), (VA) through (XA), (IB), (VB) through (XB),or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions thatare useful for inhibiting tubulin polymerization and are particularlyuseful in treating or preventing proliferative disorders, such ascancer. The invention also relates to compounds and pharmaceuticalcompositions that are useful as vascular targeting agents, particularly,in blocking, occluding, or otherwise disrupting blood flow inneovasculature.

In one embodiment, the invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(a) or R_(b) is —H and the other is an optionally substitutedaryl or an optionally substituted heteroaryl; and

R₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.

In another embodiment, the invention relates to compounds of formula(V):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₂ is defined as for formula (I); and    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl; and    -   p is 1 or 2.

In another embodiment, the invention relates to compounds of formula(VI):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is represented by the        following formula:    -   the dashed line indicates that the bond is a single bond or a        double bond;    -   X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S;    -   X₅ and X₆ are each, independently, CR₂₉ or N;    -   R₁₅ is H, halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁;    -   R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R        is an alkyl, a cycloalkyl, or an aralkyl;    -   R₂₉, for each occurrence, is independently, H or a substituent;        and    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl;    -   R₁₇, for each occurrence, is independently, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   p is 1 or 2; and    -   R₂ is defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(VII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(m) or R_(n) is —H and the other is represented by the        following formula:    -   R₂ is defined as for formula (VI);    -   R₁₈ and R₁₉ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₂₀ is an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁; and    -   X₁ and X₂ are defined as for formula (V).

In another embodiment, the invention relates to compounds of formula(VIII):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is represented by the        following formula:    -   R₂ is defined as for formula (VI),    -   R₂₂ and R₂₃, are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₂₁ is halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁; and    -   X₁ and X₂ are defined as for formula (V).

In another embodiment, the invention relates to compounds of formula(IX):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(r) is —H and the other is represented by the        following formula:    -   R₂, R₁₅, and R₂₉ are defined as for formula (VI).

In another embodiment, the invention relates to compounds of formula(X):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of Rs or Rt is —H and the other is represented by the        following formula:    -   R₂, R₁₅, R₁₆, and R₂₉ are defined as for formula (VI).

In another embodiment, the invention relates to compounds of formula(IA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl, or an optionally substituted heteroaryl; and    -   R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,        —C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or        —(R^(aa))_(q)C(O)(Y₁);    -   R^(y) is —H or lower alkyl;    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, or an optionally substituted        heteraralkyl;    -   R^(aa) is an amino acid residue or an amino acid residue analog;    -   Y is CH₂, O, or NH;    -   R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁;    -   Alk is an optionally substituted alkylene;    -   Het is an optionally substituted heteroalkyl;    -   Y₁ is a water soluble polymer with a molecular weight less than        60,000 daltons;    -   n is 1, 2, 3, or 4;    -   m is an integer from 1 to 10; and    -   q is 0 or 1.

In another embodiment, the invention relates to compounds of formula(VA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl; and    -   p is 1 or 2; and    -   R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, this invention relates to compounds of formula(VIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is represented by the        following formula:    -   the dashed line indicates that the bond is a single bond or a        double bond;    -   X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S;    -   X₅ and X₆ are each, independently, CR₂₉ or N;    -   R₁₅ is H, halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁;    -   R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R        is an alkyl, a cycloalkyl, or an aralkyl;    -   R₂₉, for each occurrence, is independently, H or a substituent    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl;    -   R₁₇, for each occurrence, is independently, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   p is 1 or 2; and    -   R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(VIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof,    -   wherein:    -   one of R_(m) or R_(n) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₁₈ and R₁₉ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₂₀ is an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁; and    -   R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(VIIIA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₂₂ and R₂₃, are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;

R₂₁ is halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; and

-   -   R_(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IXA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(r) is —H and the other is represented by the        following formula:    -   R₁₅, R₁₉, and R₂₉ are defined as for formula (VIA); and    -   R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(XA):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(s) or R_(t) is —H and the other is represented by the        following formula:    -   R₁₅, R₁₆, and R₂₉ are defined as for formula (VIA); and    -   R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IB):

-   -   or a pharmaceutically acceptable salt, solvate, or clathrate,        thereof, wherein:    -   R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a        haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an        alkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro,        an alkyl ester, or hydroxyl;    -   R₇, for each occurrence, is independently —H, an optionally        substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, or an optionally substituted        heteraralkyl;    -   one of R_(a) or R_(b) is —H and the other is an optionally        substituted aryl or an optionally substituted heteroaryl.

In another embodiment, the invention relates to compounds of formula(VB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(i) or R_(j) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R^(w) is defined as for formula (IB);    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl; and    -   p is 1 or 2.

In another embodiment, the invention relates to compounds of formula(VIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(k) or R_(l) is —H and the other is represented by the        following formula:    -   the dashed line indicates that the bond is a single bond or a        double bond;    -   X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S;    -   X₅ and X₆ are each, independently, CR₂₉ or N;    -   R₁₅ is H, halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁;    -   R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R        is an alkyl, a cycloalkyl, or an aralkyl;    -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

-   -   R₁₇, for each occurrence, is independently, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   p is 1 or 2;    -   R^(w) is defined as for formula (IB); and    -   R₂₉, for each occurrence, is independently, H or a substituent.

In another embodiment, the invention relates to compounds of formula(VIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(m) or R_(n) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;

R^(w) is defined as for formula (IB);

-   -   R₁₈ and R₁₉ are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁; and    -   R₂₀ is an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁.

In another embodiment, the invention relates to compounds of formula(VIIIB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(o) or R_(p) is —H and the other is represented by the        following formula:    -   X₁ and X₂ are each, independently, CH or N;    -   R₂₂ and R₂₃, are each, independently, halo, an optionally        substituted alkyl, an optionally substituted alkenyl, an        optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, an optionally substituted heteraralkyl,        cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a        heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;    -   R₂₁ is halo, an optionally substituted alkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        cycloalkenyl, an optionally substituted heterocyclyl, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted aralkyl, an optionally        substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl,        a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇,        —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂,        —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,        or —S(O)_(p)NR₁₀R₁₁; and    -   R^(w) is defined as for formula (IB).

In another embodiment, the invention relates to compounds of formula(IXB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(q) or R_(r) is —H and the other is represented by the        following formula:    -   R^(w) is defined as for formula (IB); and    -   R₁₅ and R₁₉ are defined as for formula (VIB).

In another embodiment, the invention relates to compounds of formula(XB):

-   -   or a pharmaceutically acceptable salt, solvate, clathrate, or        prodrug thereof, wherein:    -   one of R_(s) or R_(t) is —H and the other is represented by the        following formula:    -   R^(w) is defined as for formula (IB); and    -   R₁₅, R₁₆, and R₂₉ are defined as for formula (VIB).

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted phenyl. In one aspect of this embodiment, the phenyl grouprepresented by R_(a) or R_(b) is unsubstituted. In another aspect ofthis embodiment, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to five substituents independently selectedfrom a halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to five substituents, independently, selectedfrom an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, thephenyl group represented by R_(a) or R_(b) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(a) or R_(b) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(a) or R_(b) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted benzo[1,3]dioxolyl. In one aspect of this embodiment, thebenzo[1,3]dioxolyl group represented by R_(a) or R_(b) is unsubstituted.In another aspect of this embodiment, the benzo[1,3]dioxolyl grouprepresented by R_(a) or R_(b) is substituted with one or moresubstituents independently selected from a halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀,R₁₁, and p are defined as above. In another aspect of this embodiment,the benzo[1,3]dioxolyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the benzo[1,3]dioxolyl group represented by R_(a) or R_(b)is substituted with from one to three substituents. More preferably, thebenzo[1,3]dioxolyl group represented by R_(a) or R_(b) is substitutedwith one substituent.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted 1H-indolyl. In one aspect of this embodiment, the 1H-indolylgroup represented by R_(a) or R_(b) is unsubstituted. In another aspectof this embodiment, the 1H-indolyl group represented by R_(a) or R_(b)is substituted with one or more substituents independently selected froma halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the 1H-indolyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the 1H-indolyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, the1H-indolyl group represented by R_(a) or R_(b) is substituted with onesubstituent.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(a) or R_(b) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(a) or R_(b) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formula (I) or (V),R₂ is a substituted phenyl. In another aspect of this embodiment, thephenyl group represented by R₂ is substituted with from one to fivegroups independently selected from alkoxy, halo, alkyl, haloalkyl,haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl,1-methyl-1H-tetrazolyl, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄,—C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino,amino, alkyl amino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈,—S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or—SP(O)(OR₂₇)₂, wherein:

-   -   p is defined as above;    -   R₂₄ and R₂₇, for each occurrence are, independently, H, an        alkyl, or a cycloalkyl;    -   R₂₅ and R₂₆, for each occurrence are, independently, H, an        alkyl, or a cycloalkyl; or R₂₅ and R₂₆, together with the        nitrogen to which they are attached are a heterocyclyl or a        heteroaryl; and    -   R₂₈, for each occurrence, is an alkyl or a cycloalkyl.

In one aspect of this embodiment, the phenyl group represented by R₂ issubstituted with from one to three substituents. Preferably, the phenylrepresented by R₂ is substituted with one substituent. In someembodiments, in compounds represented by formulas (I) or (V), R₂ is asubstituted phenyl, an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted biphenyl, an optionallysubstituted 4-pyridinyl-phenyl, an optionally substituted quinolinyl, anoptionally substituted isoquinolinyl, an optionally substituted1H-indolyl, an optionally substituted pyridinyl, an optionallysubstituted oxazolyl, an optionally substituted isoxazolyl, anoptionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrrolyl, an optionally substituted pyrazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiadiazolyl, an optionally substituted oxadiazolyl, anoptionally substituted chromanyl, an optionally substitutedisochromanyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted benzothiophenyl, an optionally substituted2,3-dihydro-benzothiophenyl, an optionally substituted benzofuranyl, anoptionally substituted 2,3-dihydro-benzofuranyl, an optionallysubstituted 1H-benzoimidazolyl, an optionally substitutedbenzothiazolyl, an optionally substituted benzooxazolyl, an optionallysubstituted 1H-benzotriazolyl, an optionally substituted 1H-indazolyl,an optionally substituted 9H-purinyl, an optionally substitutedpyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl, anoptionally substituted pyrrolopyridazinyl, an optionally substitutedimidazopyrazinyl, or an optionally substituted imidazolpyridazinyl.

In some embodiments, in the compounds represented by formula (I) or (V),R₂ is an optionally substituted pyridinyl. In one aspect of thisembodiment, the pyridinyl group represented by R₂ is unsubstituted. Inanother aspect of this embodiment, the pyridinyl group represented by R₂is substituted with one or more substituents independently selected fromalkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl,1H-tetrazolyl, 1-methyl-H-tetrazolyl, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄,—OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆,guanidino, amino, alkyl amino, dialkylamino, —NR₂₄S(O)_(p)R₂₈,—S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇,—OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, wherein R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and pare defined as above. In one aspect of this embodiment, the pyridinylgroup represented by R₂ is substituted with from one to threesubstituents. Preferably, the pyridinyl represented by R₂ is substitutedwith one substituent.

In some embodiments, in the compounds represented by formula (I) or (V),R₂ is an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, anoptionally substituted biphenyl, an optionally substitutedpyridinyl-phenyl, an optionally substituted pyridinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquinolinyl, anoptionally substituted 1H-indolyl, an optionally substituted oxazolyl,an optionally substituted benzo[1,3]dioxolyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, or an optionallysubstituted benzofuranyl. In one aspect of this embodiment, R₂ isunsubstituted. In another aspect of this embodiment, R₂ is substitutedwith one or more substituents independently selected from alkoxy, halo,alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl,1-methyl-1H-tetrazolyl, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄,—C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino,amino, alkyl amino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈,—S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or—SP(O)(OR₂₇)₂, wherein R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined asabove. In one aspect of this embodiment, R₂ is substituted with from oneto three substituents. Preferably, R₂ is substituted with onesubstituent.

In some embodiments, in the compounds represented by formula (VI),(VII), (VIII), (IX), or (X), R₂ is an optionally substituted phenyl. Inone aspect of this embodiment, the phenyl group represented by R₂ isunsubstituted. In another aspect of this embodiment, the phenyl grouprepresented by R₂ is substituted with from one to five groupsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, the phenyl group represented by R₂ is substituted withfrom one to three substituents. Preferably, the phenyl represented by R₂is substituted with one substituent.

In some embodiments, in the compounds represented by formula (VI),(VII), (VIII), (IX), or (X), R₂ is an optionally substituted pyridinyl.In one aspect of this embodiment, the pyridinyl group represented by R₂is unsubstituted. In another aspect of this embodiment, the pyridinylgroup represented by R₂ is substituted with one or more substituentsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, the pyridinyl group represented by R₂ is substitutedwith from one to three substituents. Preferably, the pyridinylrepresented by R₂ is substituted with one substituent.

In some embodiments, in the compounds represented by formula (VI),(VII), (VII), (IX), or (X), R₂ is an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, anoptionally substituted pyridinyl-phenyl, an optionally substitutedpyridinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted oxazolyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, or an optionally substituted benzofuranyl. Inone aspect of this embodiment, R₂ is unsubstituted. In another aspect ofthis embodiment, R₂ is substituted with one or more substituentsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, R₂ is substituted with from one to three substituents.Preferably, R₂ is substituted with one substituent.

In some embodiments, in the compounds represented by formulas (V), (VA),or (VB), R₁₂, R₁₃, and R₁₄ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl. In one aspect of thisembodiment, R₁₂, R₁₃, and R₁₄ are each, independently, an alkoxy. Inanother aspect of this embodiment, R₁₂, R₁₃, and R₁₄ are each methoxy.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VII), (VIIIA), or (VIIIB), X₁ and X₂ areCH.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VII), (VIIIA), or (VIIIB), X₁ and X₂ areN.

In some embodiments, in the compounds represented by formula by formulas(V), (VA), (VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁is N and X₂ is CH.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁ is CH andX₂ is N.

In some embodiments, in the compounds represented by formulas (VI),(VIA), or (VIB), X₃ and X₄ are O and X₅ and X₆ are CH. In one aspect ofthis embodiment, X₃ and X₄ are O; X₅ and X₆ are CH; and R₁₅ is analkoxy, such as methoxy.

In some embodiments, in the compounds represented by formulas (VI),(VIA), or (VIB), X₃ is CH; X₄ are NR₁₆; and X₅ and X₆ are CH. In oneaspect of this embodiment, X₃ is CH; X₄ are NR₁₆; X₅ and X₆ are CH; andR₁₆ is H. In one aspect of this embodiment, X₃ is CH; X₄ are NR₁₆; X₅and X₆ are CH; and R₁₆ is a lower alkyl.

In some embodiments, in the compounds represented by formulas (VI),(VIA), (VIB), (IX), (IXA), (IXB), (X), (XA), or (XB), R₁₅ is H, alkoxy,halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, —SR₂₄, —C(O)R₂₄,—C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇,—OC(O)NR₂₅R₂₆, guanidino, amino, alkylamino, dialkylamino,—NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈,—OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; wherein R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, and p are defined as above.

In some embodiments, in the compounds represented by formulas (IX),(IXA), (IXB), (X), (XA), or (XB), R₁₅ is H, alkoxy, halo, alkyl,haloalkyl, haloalkoxy, nitro, cyano, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄,—OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆,guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈,—S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇,—OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; and R₂₉, for each occurrence, isindependently, H, alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro,cyano, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆,—NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈, and p are defined as above.

In some embodiments, in the compounds represented by formulas (VII),(VIIA), or (VIIB), R₁₈ and R₁₉ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₂₀ is an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, or an alkyl ester; wherein R₇ is defined as above.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is a substitutedphenyl represented by the following structural formula:

R₁₈ and R₁₉ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₀ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester;wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isothiazole ring.

In some embodiments, in the compounds represented by formula (VIII),(VIIIA), or (VIIIB), R₂₂ and R₂₃ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₂₁ is an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, or an alkyl ester, wherein R₇ is defined as above.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is a substitutedphenyl represented by the following structural formula:

R₂₂ and R₂₃ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₁ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester,wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isothiazole ring.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is a substitutedphenyl. In one aspect, the substituents for R_(a) or R_(b) areindependently selected from the group consisting of halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, and —S(O)_(p)NR₁₀R₁₁;

-   -   R₇ and R₈, for each occurrence, are, independently, —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;    -   R₁₀ and R₁₁, for each occurrence, are independently —H, an        optionally substituted alkyl, an optionally substituted alkenyl,        an optionally substituted alkynyl, an optionally substituted        cycloalkyl, an optionally substituted cycloalkenyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl, an optionally        substituted aralkyl, or an optionally substituted heteraralkyl;        or R₁₀ and R₁₁, taken together with the nitrogen to which they        are attached, form an optionally substituted heterocyclyl or an        optionally substituted heteroaryl; and    -   p is 1 or 2.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted heteroaryl. In one aspect, the optionally substitutedheteroaryl is selected from the group consisting of an optionallysubstituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted pyridinyl, an optionally substituted oxazolyl, anoptionally substituted isoxazolyl, an optionally substituted thiazolyl,an optionally substituted isothiazolyl, an optionally substitutedimidazolyl, an optionally substituted pyrazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiadiazolyl, an optionally substituted oxadiazolyl, anoptionally substituted chromanyl, an optionally substitutedisochromanyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted benzothiophenyl, an optionally substituted2,3-dihydro-benzothiophenyl, an optionally substituted benzofuranyl, anoptionally substituted 2,3-dihydro-benzofuranyl, an optionallysubstituted 1H-benzoimidazolyl, an optionally substitutedbenzothiazolyl, an optionally substituted benzooxazolyl, an optionallysubstituted 1H-benzotriazolyl, an optionally substituted 1H-indazolyl,an optionally substituted 9H-purinyl, an optionally substitutedpyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl, anoptionally substituted pyrrolopyridazinyl, an optionally substitutedimidazopyrazinyl, and an optionally substituted imidazolpyridazinyl.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VII IA), R^(x) is R^(aa), —C(O)YR^(z), or—C(O)NH—R^(aa). In one aspect, R^(x) is R^(aa). In another aspect, R^(x)is —C(O)YR^(z). R^(aa), R^(z), and Y are defined as for formula (IA).

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), R^(x) is R^(aa) and R^(aa) is defined as forformula (IA). In one aspect, R^(aa) is glycine, serine, alanine,phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), R^(x) is R^(aa) and R^(y) is —H, whereinR^(aa) is defined as for formula (IA). In one aspect, R^(aa) is glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, phenylalanine, tyrosine, tryptophan, aspartic acid,asparagine, glutamic acid, glutamine, arginine, histidine, lysine, orproline. In another aspect, R^(aa) is glycine, serine, alanine,phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), R^(x) is —C(O)YR^(z) and Y and R^(z) aredefined as for formula (IA). In one aspect, Y is CH₂. In another aspect,Y is O. In another aspect, Y is NH. In one aspect, R^(z) is Y₁ and Y₁ isdefined as for formula (IA). In another aspect, R^(z) is Alk-NH₂. Inanother aspect, R^(z) is Alk-C(O)OH. In another aspect, R^(z) is Het.Alk and Het and defined as for formula (IA).

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), m is 1, 2 or 3.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), Y₁ is PEG, HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-OH. In one aspect, Y₁ is PEG.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), R^(y) is —H.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), R^(y) is a lower alkyl.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), Y₁ has a molecular weight greater than 20,000daltons. In one aspect, Y₁ has a molecular weight of less than 40,000daltons, but greater than 25,000 daltons.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), Alk is an optionally substituted loweralkylene.

In some embodiments, in the compounds represented by formula (IA), (VA),(VIA), (VIIA), or (VIIIA), Het is an optionally substituted lowerheteroalkyl.

In some embodiments, in the compounds represented by formula (VA), X₁and X₂ are CH and R₁₂, R₁₃, and R₁₄ are each methoxy. In one aspect,R^(x) is R^(aa). In another aspect, R^(x) is (R^(aa))_(m). In anotheraspect, R^(x) is —R^(aa)—C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x)is —C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x) is —C(O)YR^(z). Inanother aspect, R^(x) is —C(O)NH—R^(aa). In another aspect, R^(x) is—(R^(aa))_(q)C(O)(Y₁). R^(aa), Y, R^(z), Y₁, m, n, and q are defined asfor formula (IA).

In some embodiments, in the compounds represented by formula (VA), X₁and X₂ are CH and R₁₂, R₁₃, and R₁₄ are each methoxy. In one aspect,R^(x) is R^(aa) and R^(w) is alkoxy. In another aspect, R^(x) is R^(aa)and R^(y) is —H. In another aspect, R^(x) is R^(aa), R^(w) is alkoxy,and R^(y) is —H. In another aspect, R^(x) is R^(aa), R^(w) is alkoxy,and R^(y) is —H. In another aspect, R^(x) is R^(aa), R^(w) is methoxy,and R^(y) is —H. R^(aa) is defined as for formula (IA).

In some embodiments, in the compounds represented by formula (VB), X₁and X₂ are CH; R₁₂, R₁₃, and R₁₄ are each methoxy; and R^(w) is alkoxy.In one aspect, R^(w) is methoxy.

In some embodiments, in the compounds represented by formula (IA or B),(VA or B), (VIA or B), (VIIA or B), (VIIIA or B), (IXA or B), or (XA orB), R^(w) is alkoxy. In one aspect, R^(w) is methoxy.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), R_(a) is —H. In some embodiments, in the compounds representedby formulas (I), (IA), or (IB), R_(b) is —H. In some embodiments, in thecompounds represented by formula (V), (VA), or (VB), R_(i) is —H. Insome embodiments, in the compounds represented by formulas (V), (VA), or(VB), R_(j) is —H. In some embodiments, in the compounds represented byformula (VI), (VIA), or (VIB), R_(k) is —H. In some embodiments, in thecompounds represented by formulas (VI), (VIA), or (VIB), R_(l) is —H. Insome embodiments, in the compounds represented by formula (VII), (VIIA),or (VIIB), R_(m) is —H. In some embodiments, in the compoundsrepresented by formulas (VII), (VIIA), or (VIIB), R_(n) is —H. In someembodiments, in the compounds represented by formula (VIII), (VIIIA), or(VIIIB), R_(o) is —H. In some embodiments, in the compounds representedby formulas (VIII), (VIIIA), or (VIIIB), R_(p) is —H.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   4-(4-Bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)isothiazole;-   4-(4-Iodo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]di-oxin-6-yl)-5-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isothiazole;-   4-(4-hydroxy-phenyl)-5-(3,4,5-trihydroxy-phenyl)-isothiazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Amino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4′-Methoxy-biphenyl-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-3-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-4-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Quinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-6-yl)-isothiazole;-   4-(4-Carboxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxycarbonyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(Oxazol-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-N,N-dimethylamino-phenyl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-trimethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-3-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-4-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-2-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Quinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Pyridin-4-yl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(1H-Indol-5-yl)-5-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-[1-isopropyl-1H-indol-6-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[3-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Isopropyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-pyridin-6-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(3,5-dimethoxy-4-methoxycarbonyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(3,5-diacetoxy-phenyl)-isothiazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(1-methyl-5-methoxy-1H-indol-7-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-7-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-4-yl)-isothiazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy)-isothiazole;-   4-[2-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridazin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyrimidin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridin-3-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiozol-4-yl)-phenylamine;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2-Methoxy-pyridine-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(5-Methoxy-pyridine-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    sodium salt;-   4-(2-Amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Hydroxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium    salt;-   4-(4-Phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridazin-4-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(Pyrimidin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(Pyridin-3-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3,4-Dimethoxy-5    phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(4-Hydroxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(4-Phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(1-methyl-1H-indol-5-yl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-phosphonooxy-4-methoxy-phenyl)    isothiazole, disodium salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-(N,N-dimethylamino-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-isothiazole,    hydrochloric acid salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy-phenyl]-isothiazole,    hydrochloric acid salt;-   4-(4-Methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Fluoro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Fluoro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-bromo-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-chloro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-fluoro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-nitro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-[4-(N,N,-dimethylamino)-phenyl]-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4-dimethoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4-dimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Amino-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Trifluoromethyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;    and-   4-(3,4,5-Trimethoxy-phenyl)-5-(4-bromo-phenyl)-isothiazole;    -   or pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   4-(4-Bromo-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Naphthalen-2-yl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)isothiazole;-   4-(4-Iodo-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]di-oxin-6-yl)-3-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isothiazole;-   4-(4-hydroxy-phenyl)-3-(3,4,5-trihydroxy-phenyl)-isothiazole;-   4-(4-Iodo-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Fluoro-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Amino-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4′-Methoxy-biphenyl-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-3-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-4-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(pyridine-2-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Quinolin-7-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridin-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Isoquinolin-7-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-5-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(1-ethyl-1H-indol-6-yl)-isothiazole;-   4-(4-Carboxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxycarbonyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(Oxazol-2-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Iodo-phenyl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(3-Fluoro-4-methoxy-phenyl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-N,N-dimethylamino-phenyl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(3,4,5-trimethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-3-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-4-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-[4-(Pyridin-2-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Quinolin-7-yl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Pyridin-4-yl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(Isoquinolin-7-yl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(1H-Indol-5-yl)-3-(3,4,5-triethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-5-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-[1-isopropyl-1H-indol-6-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[3-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Isopropyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(5-Methoxy-pyridin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(2,3,4-trimethoxy-pyridin-6-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(3,5-dimethoxy-4-methoxycarbonyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(3,5-diacetoxy-phenyl)-isothiazole;-   4-(2-Methoxy-pyridin-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(1-methyl-5-methoxy-1H-indol-7-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(1-ethyl-1H-indol-7-yl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-4-yl)-isothiazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy)-isothiazole;-   4-[2-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridazin-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyrimidin-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridin-3-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(3-Acetylamino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2-Methoxy-pyridine-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(5-Methoxy-pyridine-2-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Carboxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    sodium salt;-   4-(2-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Hydroxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium    salt;-   4-(4-Phosphonooxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole,    disodium salt;-   4-(4-1H-Tetrazol-5-yl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(Pyridazin-4-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(Pyrimidin-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(Pyridin-3-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Acetylamino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Amino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(2-Methoxy-pyridin-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(5-Methoxy-pyridin-2-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Carboxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(3-Amino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3,4-Dimethoxy-5    phosphonooxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;    4-(4-Hydroxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole,    sodium salt;-   4-(4-Phosphonooxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(4-1H-Tetrazol-5-yl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(1-Methyl-1H-indol-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(1-methyl-1H-indol-5-yl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(3-phosphonooxy-4-methoxy-phenyl)-isothiazole,    disodium salt;-   4-(3,4,5-Trimethoxy-phenyl)-3-(N,N-dimethylamino-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(3-amino-4-methoxy-phenyl)-isothiazole,    hydrochloric acid salt;-   4-(3,4,5-Trimethoxy-phenyl)-3-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy-phenyl]-isothiazole,    hydrochloric acid salt;-   4-(4-Methoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Fluoro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Ethyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Propyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Butyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Bromo-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Fluoro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(4-Nitro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-methoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-methyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-ethoxy-phenyl)-isothiazole;-   4-(2, 3,4,5-Tetramethoxy-phenyl)-3-(4-ethyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-propoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-propyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-butoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-butyl-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-bromo-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-chloro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-fluoro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-nitro-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-[4-(N,N,-dimethylamino)-phenyl]-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-isothiazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-isothiazole;-   4-(3,4-Dimethy-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Chloro-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Methyl-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Amino-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Trifluoromethyl-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;-   4-(4-Methoxy-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole;    and-   4-(3,4,5-Trimethoxy-phenyl)-3-(4-bromo-phenyl)-isothiazole;-   or pharmaceutically acceptable salts, solvates, clathrates, or    prodrugs thereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)    acetamide hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)propanamide;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)    butanamide;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol    4-yl)-phenyl)-3-phenylpropanamide hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol    4-yl)-phenyl)-4-methylpentanamide hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide    hydrochloride;-   1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2-methyl-propyl-ammonium    chloride;-   1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2-methyl-butyl-ammonium    chloride;-   2-hydroxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol    4-yl]-phenylcarbomoyl}-ethyl-ammonium chloride;-   C-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C-phenyl-methyl-ammonium    chloride;-   2-(1H-indol-2-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-benzofuran-2-yl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-carboxyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   3-carboxyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   3-carbamoyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   2-carbamoyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   5-amino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-pentyl-ammonium    chloride;-   4-guanidino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-butyl-ammonium    chloride;-   N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}    succinamic acid;-   4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-butyric    acid;-   2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium    chloride;-   3-(2-methoxy-ethoxy)-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-propionamide;-   3-(2-PEG)-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-propionamide;-   N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-3-(2-methylamino-ethylamino)-propionamide;-   3-PEG-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-methyl)-propionamide;-   N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-methyl)-succinamic    acid;-   {2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-carbamic    acid 2-methoxy-ethyl ester;-   2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)    phenylcarbamate-PEG;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic    acid;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)acetamide    hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)propanamide;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)    butanamide;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3-phenylpropanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4-methylpentanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide    hydrochloride;-   1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2-methyl-propyl-ammonium    chloride;-   1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2-methyl-butyl-ammonium    chloride;-   2-hydroxy-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   C-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C-phenyl-methyl-ammonium    chloride;-   2-(1H-indol-2-yl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-benzofuran-2-yl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-carboxyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   3-carboxyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   3-carbamoyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   2-carbamoyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   5-amino--{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-pentyl-ammonium    chloride;-   4-guanidino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-butyl-ammonium    chloride;-   N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol 4-yl]-phenyl}    succinamic acid;-   4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-butyric    acid;-   2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium    chloride;-   3-(2-methoxy-ethoxy)-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-propionamide;-   3-(2-PEG)-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-propionamide;-   N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-3-(2-methylamino-ethylamino)-propionamide;-   3-PEG-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-methyl)-propionamide;-   N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-methyl)-succinamic    acid;-   {2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol    4-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester;-   2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylcarbamate-PEG;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-   4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic acid;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)    propanamide hydrochloride;-   methyl 2-(2-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol    4-yl)phenylamino)-2-oxoethylamino)acetate;-   4-amino-5-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)    isothiazol-4-yl)phenylamino)-5-oxopentanoic acid hydrochloride;-   3-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol    4-yl)phenyl) propanamide hydrochloride;-   3-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl)-4-methylpentanamide    hydrochloride;-   methyl    2-(2-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylamino)-2-oxoethylamino)acetate;-   4-amino-5-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylamino)-5-oxopentanoic    acid hydrochloride;-   3-amino-N-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isothiazol    4-yl)phenyl) propanamide hydrochloride; and-   3-amino-N-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl)-4-methylpentanamide    hydrochloride;    -   or pharmaceutically acceptable salts, solvates, clathrates, or        prodrugs thereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I), (V)through (X), (IA), (VA) through (XA), (IB), (VB) through (XB), or Table1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, as an active ingredient, and a pharmaceutically acceptablecarrier or vehicle. The compositions are useful for treating orpreventing proliferative disorders such as cancer or maculardegeneration.

In another embodiment, the invention relates to methods for inhibitingtubulin polymerization in a cell comprising contacting the cell with aneffective amount of a compound represented by any one of formulas (I),(V) through (X), (IA), (VA) through (XA), (IB), (VB) through (XB), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

In another embodiment, the invention relates to methods for promotingmicrotubule depolymerization in a cell comprising contacting the cellwith an effective amount of a compound represented by any one offormulas (I), (V) through (X), (IA), (VA) through (XA), (IB), (VB)through (XB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof.

In another embodiment, the invention relates to methods for treating orpreventing a proliferative disorder in a subject in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I), (V) through (X), (IA), (VA) through (XA),(IB), (VB) through (XB), or Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I),(V) through (X), (IA), (VA) through (XA), (IB), (VB) through (XB), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof. In one aspect of this embodiment, the method involvestreating a subject with multidrug resistant cancer. In another aspect ofthis embodiment, the method involves treating a subject having a solidtumor. In another aspect of this embodiment, the method involvestreating a subject having a hematological malignancy.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I),(V) through (X), (IA), (VA) through (XA), (IB), (VB) through (XB), orTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof, and an additional therapeutic agent. In one aspect ofthis embodiment, the additional therapeutic agent is another anti-canceragent.

In another embodiment, the invention relates to methods for blocking,occluding, or otherwise disrupting blood flow in neovasculature,comprising contacting the neovasculature with an effective amount of acompound represented by any one of formulas (I), (V) through (X), (IA),(VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, and an additional therapeutic agent.

In another embodiment, the invention relates to methods blocking,occluding, or otherwise disrupting blood flow in neovasculature in asubject, comprising administering to the subject an effective amount ofa compound represented by any one of formulas (I), (V) through (X),(IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, and an additional therapeutic agent.

EXEMPLARY COMPOUNDS OF THE INVENTION

Exemplary compounds of the invention are depicted in Table 1 below.TABLE 1 Com- pound No. Structure Chemical Name 1

4-(4-Bromo-phenyl)-5-(3,4,5- trimethoxy-phenyl)- isothiazole 2

4-(4-Bromo-phenyl)-5-(3,4,5- trimethoxy-phenyl)- isothiazole 3

4-(4-methoxyphenyl)-5-(3,4,5- trimethoxyphenyl)isothiazole 4

4-(4-Iodo-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole 6

4-(4-Bromo-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole7

4-(2,3-Dihydro-benzo[1,4]di- oxin-6-yl)-5-(2-hydroxy-4-methoxy-5-propyl-phenyl)- isothiazole 8

4-(4-hydroxy-phenyl)-5- (3,4,5-trihydroxy-phenyl)- isothiazole 9

4-(4-Iodo-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 10

4-(3-Fluoro-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole11

4-(4-Nitro-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 12

4-(4-Amino-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 13

4-(4′-Methoxy-biphenyl-4-yl)- 5-(3,4,5-trimethoxy-phenyl)- isothiazole14

4-[4-(pyridine-3-yl)-phenyl]-5- (3,4,5-trimethoxy-phenyl)- isothiazole15

4-[4-(pyridine-4-yl)-phenyl]-5- (3,4,5-trimethoxy-phenyl)- isothiazole16

4-[4-(pyridine-2-yl)-phenyl]-5- (3,4,5-trimethoxy-phenyl)- isothiazole17

4-(Quinolin-7-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 18

4-(Pyridin-4-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 19

4-(Isoquinolin-7-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 20

4-(1-Methyl-1H-indol-5-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 21

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-5-yl)- isothiazole 22

4-(4-Methoxy-phenyl)-5- (1-ethyl-1H-indol-6-yl)- isothiazole 23

4-(4-Carboxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 24

4-(4-Methoxycarbonyl- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole25

4-[4-(Oxazol-2-yl)-phenyl]-5- (3,4,5-trimethoxy-phenyl)- isothiazole 26

4-(4-Methoxy-phenyl)-5- (3,4,5-triethyl-phenyl)- isothiazole 27

4-(4-Iodo-phenyl)-5- (3,4,5-triethyl-phenyl)- isothiazole 28

4-(3-Fluoro-4-methoxy- phenyl)-5-(3,4,5-triethyl- phenyl)-isothiazole 29

4-(4-Nitro-phenyl)-5- (3,4,5-triethyl-phenyl)- isothiazole 30

4-(4-N,N-dimethylamino- phenyl)-5-(3,4,5-triethyl- phenyl)-isothiazole31

4-(4-Methoxy-phenyl)-5- (3,4,5-trimethyl-phenyl)- isothiazole 32

4-[4-(Pyridin-3-yl)-phenyl]-5- (3,4,5-triethyl-phenyl)- isothiazole 33

4-[4-(Pyridin-4-yl)-phenyl]-5- (3,4,5-triethyl-phenyl)- isothiazole 34

4-[4-(Pyridin-2-yl)-phenyl]-5- (3,4,5-triethyl-phenyl)- isothiazole 35

4-(Quinolin-7-yl)-5- (3,4,5-triethyl-phenyl)- isothiazole 36

4-(Pyridin-4-yl)-5-(3,4,5- triethyl-phenyl)-isothiazole 37

4-(Isoquinolin-7-yl)-5- (3,4,5-triethyl-phenyl)- isothiazole 38

4-(1H-indol-5-yl)-5- (3,4,5-triethyl-phenyl)- isothiazole 39

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-5-yl)- isothiazole 40

4-(4-Methoxy-phenyl)-5- [1-isopropyl-1H-indol-6-yl)- isothiazole 41

4-(4-Methoxy-phenyl)-5- (2,3,4-trimethoxy-phenyl)- isothiazole 42

4-(3-Hydroxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole43

4-[3-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy- phenyl)-isothiazole 44

4-(4-Methoxy-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 45

4-(4-Isopropyl-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 46

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-5- (3,4,5-trimethoxy-phenyl)-isothiazole 47

4-(4-Ethyl-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 48

4-(5-Methoxy-pyridin-2-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 49

4-(4-Methoxy-phenyl)-5- (2,3,4-trimethoxy-pyridin-6- yl)-isothiazole 50

4-(4-Methoxy-phenyl)-5- (3,5-dimethoxy-4- methoxycarbonyl-phenyl)-isothiazole 51

4-(4-Methoxy-phenyl)-5- (3,5-diacetoxy-phenyl)- isothiazole 52

4-(2-Methoxy-pyridin-5-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 53

4-(4-Methoxy-phenyl)-5- (1-methyl-5-methoxy- 1H-indol-7-yl)-isothiazole54

4-(4-Methoxy-phenyl)-5- (1-ethyl-1H-indol-7-yl)- isothiazole 55

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-4-yl)- isothiazole 56

4-(2-Hydroxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy)- isothiazole 57

4-[2-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy- phenyl)-isothiazole 58

4-(Pyridazin-4-yl)-5-(3,4,5- trimethoxy-phenyl)- isothiazole 59

4-(Pyrimidin-5-yl)-5-(3,4,5- trimethoxy-phenyl)- isothiazole 60

4-(Pyridin-3-yl)-5-(3,4,5- trimethoxy-phenyl)- isothiazole, hydrochloricacid salt 61

4-(3-Mercapto-4-methoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole 62

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isothiazole, disodium salt 63

4-(3-Acetylamino-4-methoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole 64

2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)- isothiozol-4-yl)-phenylamine65

4-(2-Hydroxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole66

4-(2-Methoxy-pyridine-5-yl)- 5-(3,4,5-trimethoxy-phenyl)- isothiazole 67

4-(5-Methoxy-pyridine-2-yl)- 5-(3,4,5-trimethoxy-phenyl)- isothiazole 68

4-(3-Carboxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium salt 69

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isothiazole 70

4-(3-Sulfooxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium salt 71

4-(2-Amino-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole72

4-(3,4-Dimethoxy-5- phosphonooxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)-isothiazole, disodium salt 73

4-(2-Phosphonooxy-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isothiazole, disodium salt 74

4-(4-Methylsulfanyl-phenyl)- 5-(3,4,5-trimethoxy-phenyl)- isothiazole 75

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)- isothiazole, disodium salt 76

4-(3-Amino-4-methylsulfanyl- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole 77

4-(2,3-Dihydro-benzofuran-6- yl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole 78

4-(4-Hydroxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole, sodiumsalt 79

4-(4-Phosphonooxy-phenyl)- 5-(3,4,5-trimethoxy-phenyl)- isothiazole,sodium salt 80

4-(4-1H-Tetrazol-5-yl- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isothiazole81

4-[4-(1-Methyl-1H-tetrazol-5- yl)-phenyl]-5-(3,4,5- trimethoxy-phenyl)-isothiazole 82

4-(1-Methyl-1H-indol-5-yl)-5- (3,4,5-trimethoxy-phenyl)- isothiazole 83

4-(Pyridazin-4-yl)-5-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 84

4-(Pyrimidin-5-yl)-5-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 85

4-(Pyridin-3-yl)-5-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazolehydrochloric acid salt 86

4-(3-Mercapto-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 87

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 88

4-(3-Acetylamino-4- methoxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 89

4-(3-Amino-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, hydrochloric acid salt 90

4-(2-Hydroxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 91

4-(2-Methoxy-pyridin-5-yl)-5- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 92

4-(5-Methoxy-pyridin-2-yl)-5- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 93

4-(3-Carboxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, sodium salt 94

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 95

4-(3-Sulfooxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, sodium salt 96

4-(3-Amino-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 97

4-(3,4-Dimethoxy-5 phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole, disodium salt 98

4-(2-Phosphonooxy-4- methoxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isothiazole, disodium salt 99

4-(4-Methylsulfanyl-phenyl)- 5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 100

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole, disodium salt 101

4-(3-Amino-4-methylsufanyl- phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)- isothiazole 102

4-(2,3-Dihydro-benzofuran-6- yl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 103

4-(4-Hydroxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole,sodium salt 104

4-(4-Phosphonooxy-phenyl)- 5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 105

4-(4-1H-Tetrazol-5-yl-phenyl)- 5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 106

4-[4-(1-Methyl-1H-tetrazol-5- yl)-phenyl]-5-(4-methoxy-benzo[1,3]dioxol-6-yl)- isothiazole 107

4-(1-Methyl-1H-indol-5-yl)-5- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 108

4-(3,4,5-Trimethoxy-phenyl)- 5-(1-methyl-1H-indol-5-yl)- isothiazole 109

4-(3,4,5-Trimethoxy-phenyl)- 5-(3-phosphonooxy-4- methoxy-phenyl)isothiazole, disodium salt 110

4-(3,4,5-Trimethoxy-phenyl)- 5-(N,N-dimethylamino- phenyl)-isothiazole111

4-(3,4,5-Trimethoxy-phenyl)- 5-(3-amino-4-methoxy- phenyl)-isothiazole,hydrochloric acid salt 112

4-(3,4,5-Trimethoxy-phenyl)- 5-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy- phenyl]-isothiazole, hydrochloric acid salt 113

4-(4-Methoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isothiazole 114

4-(4-Methyl-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 115

4-(4-Ethxoy-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 116

4-(4-Ethyl-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 117

4-(4-Propoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isothiazole 118

4-(4-Propyl-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 119

4-(4-Butoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isothiazole 120

4-(4-Butyl-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 121

4-(4-Bromo-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 122

4-(4-Chloro-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 123

4-(4-Fluoro-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 124

4-(4-Nitro-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isothiazole 125

4-[4-(N,N-Dimethylamino)- phenyl]-5-(2,4,5-trimethoxy-phenyl)-isothiazole 126

4-(3,4-Dimethoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isothiazole 127

4-(3-Hydroxy-4-methoxy- phenyl)-5-(2,4,5-trimethoxy- phenyl)-isothiazole128

4-(3,4,5-Trimethoxy-phenyl)- 5-(2,4,5-trimethoxy-phenyl)- isothiazole129

4-(4-Methoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 130

4-(4-Methyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 131

4-(4-Ethoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 132

4-(4-Ethyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 133

4-(4-Propoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 134

4-(4-Propyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 135

4-(4-Butoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 136

4-(4-Butyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 137

4-(4-Bromo-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 138

4-(4-Chloro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 139

4-(4-Fluoro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 140

4-(4-Nitro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 141

4-[4-(N,N-Dimethylamino)- phenyl]-5-(2,3,5-trimethoxy-phenyl)-isothiazole 142

4-(3,4-Dimethoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isothiazole 143

4-(3-Hydroxy-4-methoxy- phenyl)-5-(2,3,5-trimethoxy- phenyl)-isothiazole144

4-(3,4,5-Trimethoxy-phenyl)- 5-(2,3,5-trimethoxy-phenyl)- isothiazole145

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-methoxy- phenyl)-isothiazole 146

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-methyl-phenyl)- isothiazole 147

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-ethoxy-phenyl)- isothiazole 148

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-ethyl-phenyl)- isothiazole 149

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-propoxy- phenyl)-isothiazole 150

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-propyl-phenyl)- isothiazole 151

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-butoxy-phenyl)- isothiazole 152

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-butyl-phenyl)- isothiazole 153

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-bromo-phenyl)- isothiazole 154

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-chloro-phenyl)- isothiazole 155

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-fluoro-phenyl)- isothiazole 156

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-nitro-phenyl)- isothiazole 157

4-(2,3,4,5-Tetramethoxy- phenyl)-5-[4-(N,N,- dimethylamino)-phenyl]-isothiazole 158

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3,4-dimethoxy- phenyl)-isothiazole159

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-isothiazole 160

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole 161

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-5-(3,4- dimethoxy-phenyl)-isothiazole 162

4-(3,4-Dimethy-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 163

4-(4-Chloro-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole164

4-(4-Methyl-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole165

4-(4-Amino-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole166

4-(4-Trifluoromethyl-phenyl)- 5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazote 167

4-(4-Methoxy-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 168

4-(3,4,5-Trimethoxy-phenyl)- 5-(4-bromo-phenyl)- isothiazole 169

4-(4-Bromo-phenyl)-3-(3,4,5- trimethoxy-phenyl)- isothiazole 170

4-(Naphthalen-2-yl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole171

4-(4-methoxyphenyl)-3-(3,4,5- trimethoxyphenyl)isothiazole 172

4-(4-Iodo-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole174

4-(4-Bromo-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isothiazole175

4-(2,3-Dihydro-benzo[1,4]di- oxin-6-yl)-3-(2-hydroxy-4-methoxy-5-propyl-phenyl)- isothiazole 176

4-(4-hydroxy-phenyl)-3- (3,4,5-trihydroxy-phenyl)- isothiazole 177

4-(4-Iodo-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 178

4-(3-Fluoro-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole179

4-(4-Nitro-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 180

4-(4-Amino-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 181

4-(4′-Methoxy-biphenyl-4-yl)- 3-(3,4,5-trimethoxy-phenyl)- isothiazole182

4-[4-(pyridine-3-yl)-phenyl]-3- (3,4,5-trimethoxy-phenyl)- isothiazole183

4-[4-(pyridine-4-yl)-phenyl]-3- (3,4,5-trimethoxy-phenyl)- isothiazole184

4-[4-(pyridine-2-yl)-phenyl]-3- (3,4,5-trimethoxy-phenyl)- isothiazole185

4-(4-Quinolin-7-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 186

4-(Pyridin-4-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 187

4-(Isoquinolin-7-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 188

4-(1-Methyl-1H-indol-5-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 189

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-5-yl)- isothiazole 190

4-(4-Methoxy-phenyl)-3- (1-ethyl-1H-indol-6-yl)- isothiazole 191

4-(4-Carboxy-phenyl-3- (3,4,5-trimethoxy-phenyl)- isothiazole 192

4-(4-Methoxycarbonyl- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole193

4-[4-(Oxazol-2-yl)-phenyl]-3- (3,4,5-trimethoxy-phenyl)- isothiazole 194

4-(4-Methoxy-phenyl)-3- (3,4,5-triethyl-phenyl)- isothiazole 195

4-(4-Iodo-phenyl)-3- (3,4,5-triethyl-phenyl)- isothiazole 196

4-(3-Fluoro-4-methoxy- phenyl)-3-(3,4,5-triethyl- phenyl)-isothiazole197

4-(4-Nitro-phenyl)-3- (3,4,5-triethyl-phenyl)- isothiazole 198

4-(4-N,N-dimethylamino- phenyl)-3-(3,4,5-triethyl- phenyl)-isothiazole199

4-(4-Methoxy-phenyl)-3- (3,4,5-trimethyl-phenyl)- isothiazole 200

4-[4-(Pyridin-3-yl)-phenyl]-3- (3,4,5-triethyl-phenyl)- isothiazole 201

4-[4-(Pyridin-4-yl)-phenyl]-3- (3,4,5-triethyl-phenyl)- isothiazole 202

4-[4-(Pyridin-2-yl)-phenyl]-3- (3,4,5-triethyl-phenyl)- isothiazole 203

4-(4-Quinolin-7-yl)-3- (3,4,5-triethyl-phenyl)- isothiazole 204

4-(Pyridin-4-yl)-3-(3,4,5- triethyl-phenyl)-isothiazole 205

4-(Isoquinolin-7-yl)-3- (3,4,5-triethyl-phenyl)- isothiazole 206

4-(1H-Indol-5-yl)-3- (3,4,5-triethyl-phenyl)- isothiazole 207

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-5-yl)- isothiazole 208

4-(4-Methoxy-phenyl)-3- [1-isopropyl-1H-indol-6-yl)- isothiazole 209

4-(4-Methoxy-phenyl)-3- (2,3,4-trimethoxy-phenyl)- isothiazole 210

4-(3-Hydroxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole211

4-[3-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy- phenyl)-isothiazole 212

4-(4-Methoxy-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 213

4-(4-Isopropyl-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 214

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-3- (3,4,5-trimethoxy-phenyl)-isothiazole 215

4-(4-Ethyl-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 216

4-(5-Methoxy-pyridin-2-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 217

4-(4-Methoxy-phenyl)-3- (2,3,4-trimethoxy-pyridin-6- yl)-isothiazole 218

4-(4-Methoxy-phenyl)-3- (3,5-dimethoxy-4- methoxycarbonyl-phenyl)-isothiazole 219

4-(4-Methoxy-phenyl)-3- (3,5-diacetoxy-phenyl)- isothiazole 220

4-(2-Methoxy-pyridin-5-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 221

4-(4-Methoxy-phenyl)-3- (1-methyl-5-methoxy- 1H-indol-7-yl)-isothiazole222

4-(4-Methoxy-phenyl)-3- (1-ethyl-1H-indol-7-yl)- isothiazole 223

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-4-yl)- isothiazole 224

4-(2-Hydroxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy)- isothiazole 225

4-[2-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy- phenyl)-isothiazole 226

4-(Pyridazin-4-yl)-3-(3,4,5- trimethoxy-phenyl)- isothiazole 227

4-(Pyrimidin-5-yl)-3-(3,4,5- trimethoxy-phenyl)- isothiazole 228

4-(Pyridin-3-yl)-3-(3,4,5- trimethoxy-phenyl)- isothiazole, hydrochloricacid salt 229

4-(3-Mercapto-4-methoxy- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole 230

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isothiazole, disodium salt 231

4-(3-Acetylamino-4-methoxy- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole 232

4-(3-Amino-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole233

4-(2-Hydroxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole234

4-(2-Methoxy-pyridine-5-yl)- 3-(3,4,5-trimethoxy-phenyl)- isothiazole235

4-(5-Methoxy-pyridine-2-yl)- 3-(3,4,5-trimethoxy-phenyl)- isothiazole236

4-(3-Carboxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium salt 237

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isothiazole 238

4-(3-Sulfooxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole, sodium salt 239

4-(2-Amino-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole240

4-(3,4-Dimethoxy-5- phosphonooxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)-isothiazole, disodium salt 241

4-(2-Phosphonooxy-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isothiazole, disodium salt 242

4-(4-Methylsulfanyl-phenyl)- 3-(3,4,5-trimethoxy-phenyl)- isothiazole243

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)- isothiazole, disodium salt 244

4-(3-Amino-4-methylsulfanyl- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole 245

4-(2,3-Dihydro-benzofuran-6- yl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole 246

4-(4-Hydroxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole, sodiumsalt 247

4-(4-Phosphonooxy-phenyl)- 3-(3,4,5-trimethoxy-phenyl)- isothiazole,disodium salt 248

4-(4-1H-Tetrazol-5-yl- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isothiazole249

4-[4-(1-Methyl-1H-tetrazol-5- yl)-phenyl]-3-(3,4,5- trimethoxy-phenyl)-isothiazole 250

4-(1-Methyl-1H-indol-5-yl)-3- (3,4,5-trimethoxy-phenyl)- isothiazole 251

4-(Pyridazin-4-yl)-3-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 252

4-(Pyrimidin-5-yl)-3-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 253

4-(Pyridin-3-yl)-3-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole,hydrochloric acid salt 254

4-(3-Mercapto-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 255

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 256

4-(3-Acetylamino-4- methoxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 257

4-(3-Amino-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, hydrochloric acid salt 258

4-(2-Hydroxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 259

4-(2-Methoxy-pyridin-5-yl)-3- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 260

4-(5-Methoxy-pyridin-2-yl)-3- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 261

4-(3-Carboxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, sodium salt 262

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole 263

4-(3-Sulfooxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole, sodium salt 264

4-(3-Amino-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 265

4-(3,4-Dimethoxy-5 phosphonooxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole, disodium salt 266

4-(2-Phosphonooxy-4- methoxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isothiazole, disodium salt 267

4-(4-Methylsulfanyl-phenyl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 268

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6- yl)-isothiazole, disodium salt 269

4-(3-Amino-4-methylsulfanyl- phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)- isothiazole 270

4-(2,3-Dihydro-benzofuran-6- yl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 271

4-(4-Hydroxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6- yl)-isothiazole,sodium salt 272

4-(4-Phosphonooxy-phenyl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 273

4-(4-1H-Tetrazol-5-yl-phenyl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isothiazole 274

4-[4-(1-Methyl-1H-tetrazol-5- yl)-phenyl]-3-(4-methoxy-benzo[1,3]dioxol-6-yl)- isothiazole 275

4-(1-Methyl-1H-indol-5-yl)-3- (4-methoxy-benzo[1,3]dioxol-6-yl)-isothiazole 276

4-(3,4,5-Trimethoxy-phenyl)- 3-(1-methyl-1H-indol-5-yl)- isothiazole 277

4-(3,4,5-Trimethoxy-phenyl)- 3-(3-phosphonooxy-4-methoxy-phenyl)-isothiazole, disodium salt 278

4-(3,4,5-Trimethoxy-phenyl)- 3-(N,N-dimethylamino- phenyl)-isothiazole279

4-(3,4,5-Trimethoxy-phenyl)- 3-(3-amino-4-methoxy- phenyl)-isothiazole,hydrochloric acid salt 280

4-(3,4,5-Trimethoxy-phenyl)- 3-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy- phenyl]-isothiazole, hydrochloric acid salt 281

4-(4-Methoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isothiazole 282

4-(4-Methyl-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 283

4-(4-Ethoxy-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 284

4-(4-Ethyl-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 285

4-(4-Propoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isothiazole 286

4-(4-Propyl-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 287

4-(4-Butoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isothiazole 288

4-(4-Butyl-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 289

4-(4-Bromo-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 290

4-(4-Chloro-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 291

4-(4-Fluoro-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 292

4-(4-Nitro-phenyl)-3-(2,4,5- trimethoxy-phenyl)- isothiazole 293

4-[4-(N,N-Dimethylamino)- phenyl]-3-(2,4,5-trimethoxy-phenyl)-isothiazole 294

4-(3,4-Dimethoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isothiazole 295

4-(3-Hydroxy-4-methoxy- phenyl)-3-(2,4,5-trimethoxy- phenyl)-isothiazole296

4-(3,4,5-Trimethoxy-phenyl)- 3-(2,4,5-trimethoxy-phenyl)- isothiazole297

4-(4-Methoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 298

4-(4-Methyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 299

4-(4-Ethoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 300

4-(4-Ethyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 301

4-(4-Propoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 302

4-(4-Propyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 303

4-(4-Butoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 304

4-(4-Butyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 305

4-(4-Bromo-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 306

4-(4-Chloro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 307

4-(4-Fluoro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 308

4-(4-Nitro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 309

4-[4-(N,N-Dimethylamino)- phenyl]-3-(2,3,5-trimethoxy-phenyl)-isothiazole 310

4-(3,4-Dimethoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isothiazole 311

4-(3-Hydroxy-4-methoxy- phenyl)-3-(2,3,5-trimethoxy- phenyl)-isothiazole312

4-(3,4,5-Trimethoxy-phenyl)- 3-(2,3,5-trimethoxy-phenyl)- isothiazole313

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-methoxy- phenyl)-isothiazole 314

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-methyl-phenyl)- isothiazole 315

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-ethoxy-phenyl)- isothiazole 316

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-ethyl-phenyl)- isothiazole 317

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-propoxy- phenyl)-isothiazole 318

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-propyl-phenyl)- isothiazole 319

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-butoxy-phenyl)- isothiazole 320

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-butyl-phenyl)- isothiazole 321

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-bromo-phenyl)- isothiazole 322

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-chloro-phenyl)- isothiazole 323

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-fluoro-phenyl)- isothiazole 324

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-nitro-phenyl)- isothiazole 325

4-(2,3,4,5-Tetramethoxy- phenyl)-3-[4-(N,N,- dimethylamino)-phenyl]-isothiazole 326

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3,4-dimethoxy- phenyl)-isothiazole327

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-isothiazole 328

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3,4,5-trimethoxy-phenyl)-isothiazole 329

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-3-(3,4- dimethoxy-phenyl)-isothiazole 330

4-(3,4-Dimethy-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 331

4-(4-Chloro-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isothiazole332

4-(4-Methyl-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isothiazole333

4-(4-Amino-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isothiazole334

4-(4-Trifluoromethyl-phenyl)- 3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 335

4-(4-Methoxy-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl-phenyl)-isothiazole 336

4-(3,4,5-Trimethoxy-phenyl)- 3-(4-bromo-phenyl)- isothiazole 337

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl) acetamide hydrochloride 338

2-amino-3-hydroxy-N- (2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)- phenyl)propanamide hydrochloride 339

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl)-phenyl)propanamide 340

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4- (methylthio)butanamide hydrochloride 341

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl) butanamide 342

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3- phenylpropanamide hydrochloride 343

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4- methylpentanamide hydrochloride 344

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3-(4- methoxyphenyl) propanamide hydrochloride345

2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol- 4-yl)-phenyldihydrogen phosphate 346

Sodium 2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl)-phenyl phosphate 347

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 348

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 349

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 350

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 351

2-hydroxy-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 352

2-hydroxy-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 353

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 354

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 355

C-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 356

C-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 357

2-(1H-indol-2-yl)-1-{2-methoxy- 5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammonium chloride 358

2-(1H-indol-2-yl)-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 359

2-benzofuran-2-yl-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 360

2-benzofuran-2-yl-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 361

2-carboxyl-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 362

2-carboxyl-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 363

3-carboxyl-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 364

3-carboxyl-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 365

3-carbamoyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 366

3-carbamoyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 367

2-carbamoyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 368

2-carbamoyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 369

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 370

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 371

5-amino-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 372

5-amino-1-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 373

4-guanidino-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 374

4-guanidino-1-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 375

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}succinamic acid 376

4-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}- butyric acid 377

2-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-ethyl- ammonium chloride 378

3-(2-methoxy-ethoxy)-N-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenyl}-propionamide 379

3-(2-PEG)-N-{2-methoxy-5- [5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}- propionamide 380

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-3-(2- methylamino-ethylamino)- propionamide 381

3-PEG-N-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbamoyl}-methyl)- propionamide 382

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}- methyl)-succinamic acid 383

{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester 384

2-methoxy-5-(5-(3,4,5- trimethoxyphenyl)isothiazol-4-yl)-phenylcarbamate-PEG 385

3-amino-N-[4-guanadino-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]- succinamic acid 386

3-amino-N-[4-guanadino-1-{2- methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]- succinamic acid 387

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl) propanamide hydrochloride 388

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl)-phenyl)acetamide hydrochloride 389

2-amino-3-hydroxy-N-(2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl)-phenyl)propanamide hydrochloride 390

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl)-phenyl)propanamide 391

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4- (methylthio)butanamide hydrochloride 392

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl) butanamide 393

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3- phenylpropanamide hydrochloride 394

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-4- methylpentanamide hydrochloride 395

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl)-3-(4- methoxyphenyl) propanamide hydrochloride396

2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol- 4-yl)- phenyldihydrogen phosphate 397

Sodium 2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl)-phenyl phosphate 398

1-{2-methoxy-3-[5-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 399

1-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 400

1-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 401

1-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 402

2-hydroxy-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 403

2-hydroxy-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 404

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 405

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 406

C-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 407

C-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 408

2-(1H-indol-2-yl)-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammonium chloride 409

2-(1H-indol-2-yl)-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 410

2-benzofuran-2-yl-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 411

2-benzofuran-2-yl-1-{2- methoxy-5-[3-(3,4 5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 412

2-carboxyl-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 413

2-carboxyl-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 414

3-carboxyl-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 415

3-carboxyl-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 416

3-carbamoyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 417

3-carbamoyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 418

2-carbamoyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 419

2-carbamoyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 420

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[3-(3,4 5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 421

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[3-(3,4 5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbomoyl}-ethyl- ammoniumchloride 422

5-amino-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 423

5-amino-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 424

4-guanidino-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 425

4-guanidino-1-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 426

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}succinamic acid 427

4-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}- butyric acid 428

2-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}-ethyl- ammonium chloride 429

3-(2-methoxy-ethoxy)-N-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenyl}-propionamide 430

3-(2-PEG)-N-{2-methoxy-5- [3-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}- propionamide 431

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-3-(2- methylamino-ethylamino)- propionamide 432

3-PEG-N-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isothiazol-4-yl]-phenylcarbamoyl}-methyl)- propionamide 433

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenylcarbamoyl}- methyl)-succinamic acid 434

{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isothiazol-4-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester 435

2-methoxy-5-(3-(3,4,5- trimethoxyphenyl)isothiazol-4-yl)phenylcarbamate-PEG 436

3-amino-N-[4-guanadino-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]- succinamic acid 437

3-amino-N-[4-guanadino-1-{2- methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isothiazol- 4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]- succinamic acid 438

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isothiazol-4-yl)-phenyl) propanamide hydrochloride 439

methyl 2-(2-(2-methoxy-5-(5-(3,4,5- trimethoxyphenyl)isothiazol-4-yl)phenylamino)- 2-oxoethylamino)acetate 440

4-amino-5-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylamino)- 5-oxopentanoic acid hydrochloride 441

3-amino-N-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl) propanamide hydrochloride 442

3-amino-N-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl)-4- methylpentanamide hydrochloride 443

methyl 2-(2-(2-methoxy-5-(3-(3,4,5- trimethoxyphenyl)isothiazol-4-yl)phenylamino)-2- oxoethylamino)acetate 444

4-amino-5-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylamino)- 5-oxopentanoic acid hydrochloride 445

3-amino-N-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl) propanamide hydrochloride 446

3-amino-N-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenyl)-4- methylpentanamide hydrochlorideMethods of Making the Compounds of the Invention

The compounds of the invention can be made by the methods describedherein in Example 1. In addition, the compounds of the invention can beprepared using the methods described in Olivera, et al., J. Org. Chem.(2000), 65:6398-6411; Olivera, et al., Tetrahedron (2002), 58:3021-3037;Dominguez, et al., J. Org. Chem. (1996), 61:5435-5439; Olivera, et al.,Tet. Let. (1999), 40:3479-3480; Khilya, et al. Ukrainskii KhimicheskiiZhumal (Russian Edition) (1990), 56(3);280-286. The entire teachings ofthese references are incorporated herein by reference.

Methods of Treatment and Prevention

In one embodiment, the invention provides a method of inhibiting tubulinpolymerization in a cell, comprising contacting the cell with aneffective amount of a compound of any one of formulas (I), (V) through(X), (IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, or a pharmaceutical composition comprising a compound of anyone of formulas (I), (V) through (X), (IA), (VA) through (XA), (IB),(VB) through (XB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof. Inhibition of tubulinpolymerization can be determined by determining the IC₅₀ for tubulinpolymerization inhibition for a compound as described above, or by usingthe methods described in Examples 4 and 5, herein.

In another embodiment, the invention provides a method of treating aproliferative disorder, such as cancer, in a subject in need thereof,comprising administering to the subject an effective amount of acompound of any one of formulas (I), (V) through (X), (IA), (VA) through(XA), (IB), (VB) through (XB), or Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, and prodrug thereof, or apharmaceutical composition comprising a compound of any one of formulas(I), (V) through (X), (IA), (VA) through (XA), (IB), (VB) through (XB),or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,and prodrug thereof. Such patients may be treatment naïve or mayexperience partial or no response to conventional therapies.

In another embodiment, the invention provides a method of blocking,occluding, or otherwise disrupting blood flow in neovasculature, in asubject in need thereof, comprising administering to the subject aneffective amount of a compound of any one of formulas (I), (V) through(X), (IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, or a pharmaceutical composition comprising a compound of anyone of formulas (I), (V) through (X), (IA), (VA) through (XA), (IB),(VB) through (XB), or Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof.

Responsiveness to treatment with the compounds of the invention in thecase of proliferative disorders, can be measured by reduction in theextent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. Responsivenessto treatment with the compounds of the invention in the case of cancer,can be measured by a reduction in tumor mass, a reduction in the rate oftumor growth, a reduction in metastasis, a reduction in the severity ofthe symptoms associated with the cancer and/or an increase in thelongevity of the subject compared with the absence of the treatment.

Combination Therapies

The invention also provides methods of preventing, treating, managing,or ameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof, said methods comprising administering to a subject inneed thereof one or more compounds of the invention and one or moreother therapies (e.g., one or more prophylactic or therapeutic agentsthat are currently being used, have been used, are known to be useful orin development for use in the prevention, treatment or amelioration of aproliferative disorder, such as cancer, or one or more symptomsassociated with said proliferative disorder).

The prophylactic or therapeutic agents of the combination therapies ofthe invention can be administered sequentially or concurrently. In aspecific embodiment, the combination therapies of the invention compriseone or more compounds and at least one other therapy (e.g., anotherprophylactic or therapeutic agent) which has the same mechanism ofaction as said compounds (e.g., a therapeutic agent that inhibitstubulin polymerization). In another specific embodiment, the combinationtherapies of the invention comprise one or more compounds of theinvention and at least one other therapy (e.g., another prophylactic ortherapeutic agent) which has a different mechanism of action than saidcompounds. In certain embodiments, the combination therapies of thepresent invention improve the prophylactic or therapeutic effect of oneor more compounds of the invention by functioning together with thecompounds to have an additive or synergistic effect. In certainembodiments, the combination therapies of the present invention reducethe side effects associated with the therapies (e.g., prophylactic ortherapeutic agents). In certain embodiments, the combination therapiesof the present invention reduce the effective dosage of one or more ofthe therapies.

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject, preferably a human subject, in the samepharmaceutical composition. In alternative embodiments, the prophylacticor therapeutic agents of the combination therapies can be administeredconcurrently to a subject in separate pharmaceutical compositions. Theprophylactic or therapeutic agents may be administered to a subject bythe same or different routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to prevent, treat, manage, or ameliorate a proliferativedisorder, such as cancer, or one or more symptom thereof. In accordancewith the invention, pharmaceutical compositions of the invention mayalso comprise one or more other agents (e.g., prophylactic ortherapeutic agents which are currently being used, have been used, orare known to be useful in the prevention, treatment or amelioration of aproliferative disorder or a symptom thereof.

The invention provides methods for preventing, managing, treating orameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof in a subject refractory (either completely orpartially) to existing agent therapies for such a proliferativedisorder, said methods comprising administering to said subject a doseof an effective amount of one or more compounds of the invention and adose of an effective amount of one or more therapies (e.g., one or moreprophylactic or therapeutic agents useful for the prevention, treatment,management, or amelioration of a proliferative disorder or a symptomthereof). The invention also provides methods for preventing, treating,managing, or ameliorating a proliferative disorder or a symptom thereofby administering one or more compounds of the invention in combinationwith any other therapy(ies) to patients who have proven refractory toother therapies but are no longer on these therapies.

The compounds of the invention and/or other therapies can beadministered to a subject by any route known to one of skill in the art.Examples of routes of administration include, but are not limited to,parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,inhalation), intranasal, transdermal (topical), transmucosal, and rectaladministration.

Agents Useful In Combination With Compounds of the Invention;

Anticancer agents that can be co-administered with the compounds of theinvention include Taxol™, also referred to as “paclitaxel”, which is awell-known anti-cancer drug which acts by enhancing and stabilizingmicrotubule formation, and analogs of Taxol™, such as Taxotere™.Compounds that have the basic taxane skeleton as a common structuralfeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules and may be useful fortreating cancer in combination with the compounds of the invention.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridline; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferongamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride. Other anti-cancer drugs that can beemployed in combination with the compounds of the invention include:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with the compounds of the invention include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96 F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Pharmaceutical Compositions

The present invention provides compositions for the treatment,prophylaxis, and amelioration of proliferative disorders, such ascancer. In a specific embodiment, a composition comprises one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition of the invention comprises one or more prophylactic ortherapeutic agents other than a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrugthereof. In another embodiment, a composition of the invention comprisesone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate or prodrug thereof, and one or moreother prophylactic or therapeutic agents. In another embodiment, thecomposition comprises a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and formulated in such a way thata given pharmaceutical composition or dosage form can be used to treator prevent proliferative disorders, such as cancer. Preferredpharmaceutical compositions and dosage forms comprise a compound offormulas (I), (V) through (X), (IA), (VA) through (XA), (IB), (VB)through (XB), or Table 1, or a pharmaceutically acceptable prodrug,salt, solvate, clathrate, hydrate, or prodrug thereof, optionally incombination with one or more additional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP)SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Oral Dosage Forms:

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990)18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms:

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormulas (I), (V) through (X), (IA), (VA) through (XA), (IB), (VB)through (XB), or Table 1, or a pharmaceutically acceptable salt,solvate, hydrate, clathrate, or prodrug thereof, in spheroids whichfurther comprise microcrystalline cellulose and, optionally,hydroxypropylmethyl-cellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entirely of whichis incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formulas (I), (V) through (X),(IA), (VA) through (XA), (IB), (VB) through (XB), or Table 1, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, by weight, about 50% to about 94% microcrystallinecellulose, NF, by weight, and optionally from about 0.25% to about 1% byweight of hydroxypropyl-methylcellulose, USP, wherein the spheroids arecoated with a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

Parenteral Dosage Forms:

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms:

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage & Frequency of Administration:

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of aproliferative disorder, such as cancer, or one or more symptoms thereof,will vary with the nature and severity of the disease or condition, andthe route by which the active ingredient is administered. The frequencyand dosage will also vary according to factors specific for each patientdepending on the specific therapy (e.g., therapeutic or prophylacticagents) administered, the severity of the disorder, disease, orcondition, the route of administration, as well as age, body, weight,response, and the past medical history of the patient. Effective dosesmay be extrapolated from dose-response curves derived from in vitro oranimal model test systems. Suitable regiments can be selected by oneskilled in the art by considering such factors and by following, forexample, dosages reported in the literature and recommended in thePhysician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose or preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent proliferative disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such proliferative disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a proliferative disorders, such as cancer, or one or moresymptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's bodyweight. In another embodiment, the dosage of the composition of theinvention or a compound of the invention administered to prevent, treat,manage, or ameliorate a proliferative disorders, such as cancer, or oneor more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg,0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mgto 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg,1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) Ed.,2003, Medical Economics Co., Inc., Montvale, N.J., which areincorporated herein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered less than 5 minutesapart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart,at about 1 to about 2 hours apart, at about 2 hours to about 3 hoursapart, at about 3 hours to about 4 hours apart, at about 4 hours toabout 5 hours apart, at about 5 hours to about 6 hours apart, at about 6hours to about 7 hours apart, at about 7 hours to about 8 hours apart,at about 8 hours to about 9 hours apart, at about 9 hours to about 10hours apart, at about 10 hours to about 11 hours apart, at about 11hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96hours apart, or 96 hours to 120 hours part. In one embodiment, two ormore therapies (e.g., prophylactic or therapeutic agents) areadministered within the same patient visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy, involves theadministration of a first therapy (e.g., a first prophylactic ortherapeutic agents) for a period of time, followed by the administrationof a second therapy (e.g., a second prophylactic or therapeutic agents)for a period of time, followed by the administration of a third therapy(e.g., a third prophylactic or therapeutic agents) for a period of timeand so forth, and repeating this sequential administration, i.e., thecycle in order to reduce the development of resistance to one of theagents, to avoid or reduce the side effects of one of the agents, and/orto improve the efficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 μg/kg,preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES

Experimental Rationale Without wishing to be bound by theory, it isbelieved that the compounds of this invention inhibit tubulinpolymerization and/or target vasculature and, therefore, can be used toinhibit undesirable cellular proliferation in disorders such as cancer.The examples that follow demonstrate these properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention Compound 3:4-(4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole

100 mg of 4-(4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole(1a) in EyOH (10 mL) was hydrogenated under the catalysis of 10% Pd onwet carbon at rt overnight. Removal of catalyst and solvent gave3-amino-2-(4-methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (2a,75 mg) as colorless oil.

74 mg of 2a was dissolved in THF (10 mL) and sodium bicarbonate (0.2 g)and P₂S₅ (0.15 g) was added followed by iodine (0.15 g). The mixture wasstirred at rt for 24 h. Removal of solvent and purified the mixture withrepeated column chromatography gave4-(4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole (3a, 4 mg)as white solid.

Compound 3: 4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isothiazole

¹H-NMR (CDCl₃) δ (ppm) 8.47 (s, 1H), 7.3 (d, 2H, J=8), 6.9 (d, 2H, J=8),6.52 (s, 2H), 3.87 (s, 3H), 3.82(s, 3H), 3.70 (s, 6H); ESMS clcd forC₁₉H₁₉NO₄S: 357.1; Found: 358.0 (M+H)⁺.

Compound 64:

2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isothiazol-4-yl]-phenylamine

¹H-NMR (CDCl₃) δ (ppm) 8.44 (s, 1H), 6.7 (m, 3H), 6.57 (s, 2H), 3.87 (s,3H), 3.86(s, 3H), 3.8 (br, 2H), 3.72 (s, 6H); ESMS clcd for C₁₉H₂₀N₂O₄S:372.1; Found: 373.1 (M+H)⁺.

Synthesis of 4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole(1) Synthesis of3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone

To a stirred solution of p-anislaldehyde (1.36 g, 10 mmol) and1-(3,4,5-trimethoxy-phenyl)-ethanone (2.1 g, 10 mmol) in ethyl alcohol(EtOH) (10 mL) was added a 50% solution of NaOH in H₂O (1 mL). After thereaction had proceeded to completion, volatile components were removedunder reduced pressure and the residue was taken up with ethyl acetate(EtOAc) (50 mL). The EtOAc layer was washed with H₂O (2×30 mL) and thendried with Na₂SO₄. After removal of EtOAc, the product was precipitatedout from EtOH/H₂O. Solid material collected by filtration and was washedby H₂O (20 mL) and 95% ethyl alcohol (10 mL). The product,3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (2.8 g, 85%yield), was obtained as a yellow solid. ¹H-NMR δ 3.85 (s, 3H), 3.90 (s,3H), 3.95 (s, 6H), 6.95 (d, 2H, J=8), 7.28(s, 2H), 7.39 (d, 1H, J=15),7.65 (d, 2H, J=8), 7.85 (d, 1H, J=15)ppm.

(2) Synthesis of[3-(4-Methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone

To a stirred solution of3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (1.64 g, 5mmol) and 1 N NaOH (2.52 mL) in 95% EtOH (22 mL) was added a coldsolution of 30% H₂O₂ (0.77 mL) at room temperature. After 72 h stirring,the precipitated material was collected by filtration and washed with95% EtOH to afford[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone as awhite solid (1.38 g, yield 80%). ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 3.92 (s,6H), 3.95 (s, 3H), 4.05 (d, 1H, J=2), 4.20 (1H, J=2), 6.95 (d, 2H, J=7),7.25-7.35 (m, 4H)ppm.

(3) Synthesis of4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole

To a stirred solution of[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone (0.5g, 1.45 mmol) in dry ether (15 mL) was added BF₃.Et₂O (2.52 mL) slowly.After the addition, it was heated to reflux for 1 h. After the reactionmixture had cooled to room temperature, it was poured into ice-H₂O (100mL). The etheral layer was separated and the aquous layer was extractedwith ether (10 mL×3). The combined ether layers were washed with H₂O (20mL×2) and concentrated to dryness. The residue was then transferred withEtOH (3 mL) to a flask suited for a microwave reactor, and hydroxylaminehydrochloride (0.32 g, 4.6 mmol) and pyridine (1 mL) were added. Themixture was heated and stirred in a microwave reactor at 130° C. for 30min. The reaction mixture was then cooled to room temperature and pouredinto ice-H₂O (20 mL). The solid material was collected and washed withH₂O. After preparative HPLC or repeated solvating gas chromatography(SGC) (hexane to 14% Hexane/EtOAc), the product4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole was obtainedas a light yellow solid. ¹H-NMR (CDCl₃) δ 3.70 (s, 6H), 3.82 (s, 3H),3.85 (s, 3H), 6.85 (s, 2H), 6.94 (d, 2H, J=8), 7.33 (d, 2H, J=8), 8.30(s, 1H) ppm; ESMS calcd for C₁₉H₁₉NO₅: 341.0; found: 342.0 (M+H⁺).

Compound 216: 2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylcarbamate-PEG

A solution of2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)anilinehydrochloride (300 mg, 0.76 mmol) and triethylamine (0.22 mL, 1.60 mmol)in dichloromethane (3 mL) is added slowly to a solution of triphosgene(77 mg, 0.26 mmol) in dichloromethane (5 mL) at 0° C. under nitrogenatmosphere. The reaction mixture is stirred for 30 min at roomtemperature, and then cooled to 0° C. before the addition of PEG (1.53g, 0.76 mmol) and triethylamine (0.12 mL, 0.77 mmol) in 2 ml ofdichloromethane. The resulting reaction mixture is stirred for 3 h. andwashed with NaHCO₃ solution. The aqueous layer is extracted withdichloromethane (2×), and the combined organic layers are washed withsaturated NaCl solution, dried over Na₂SO₄ and evaporated. The crudeproduct is purified by silica gel column chromatography (20% MeOH in EA)to give desired product2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isothiazol-4-yl)phenylcarbamate-PEG.Synthesis of Amino-Acid Derivatives

({2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-carbamicacid tert-butyl ester (2)

To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole(0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonylchloride (0.158 mL, 2 mmol) is added. Ice bath is removed, 1 (0.4 g, 1mmol) is added as a solid, followed by thriethylamine (0.144 mL, 2.02mmol), and the reaction mixture is stirred at 40-50° C. overnight. Aresulted solution is decanted from a solid, a flask rinsed with EtOAc,and a combined organic solution is washed with saturated ammoniumchloride solution, then twice with water, brine and dried over anhydroussodium sulfate. The solution is filtered out through a celite pad,concentrated and the residue is dissolved in 2-propanol (3 mL) withheating, and hexane (1-2 mL) is added drop-wise to start precipitation.In 1 hour a solid is filtered out, washed with 1:1 Hexane:ether mixture(10 ml×2) and vacuum-dried to give 2.

2-Amino-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-acetamide(3)

To a solution of 2 in THF (6 mL) a 1M solution of HCl in ethanol (17 mL)is added, and a resulted solution is stirred overnight at roomtemperature to form a suspension with product partly precipitated out.The reaction mixture is concentrated under reduced pressure keepingtemperature below 45° C. to ˜10 mL volume. A solid is filtered out,washed with ether (5 ml×2), hexane (5 mL) and vacuum-dried to give 3.

Example 2 Cytotoxicity of Compounds of the Invention in MultidrugResistant Cell Lines

The in vitro cytotoxicity of the compounds of the invention wasdetermined in the following human cell lines: HL-60 (T-cell leukemia),MES-SA and MES-SA/DX5 (uterine sarcoma). MES-SA is a model of uterinesarcoma, and the cell are sensitive to a number of chemotherapeuticagents including doxorubicin, dactinomycin, mitomycin C, taxol andbleomycin, but resistant to vinblastine and cisplatin. MES-SA/DX5 wasestablished in the presence of increasing concentrations of doxorubicin.The cells express high levels of mdr-1 mRNA and p-glycoprotein andexhibit cross resistance to more than fifteen chemotherapeutic agentsincluding taxol, etoposide, mitomycin C, colchicine, vinblastine,dactinomycin, 5-fluorouracil, methotrexate and so on. All cells werepurchased from ATCC.

The cell lines were maintained in RPMI1640 (GIBCO) supplemented with 10%FCS, 100 units/mL penicillin, 100 ug/ml streptomycin, and 2 mML-glutamine. Cells were split every third day and diluted to aconcentration of 2×105 cells/mL one day before the experiment wasperformed. All experiments were performed on exponentially growing cellcultures. Cell densities were 2.5×10⁴ cells/mL in all experiments.

Compounds of the invention were prepared by dissolving the compound at aconcentration of 10 mM in 100% DMSO. Final concentrations 10, 1, 0.1,0.01 and 0.001 μM were obtained by diluting the stock solution directlyinto the tissue culture medium. Cells were incubated with varyingconcentrations of compound 3 for 72 hours and the IC₅₀ was determined byMTS (i.e. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)assay. IC₅₀ in this context stands for the concentration of compoundrequired to inhibit 50% tumor cell growth. Surprisingly, Compounds 3 and64 exhibited lower IC₅₀s for multidrug resistant cell line MES/SA-DX5than for non-multidrug resistant lines HL 60 and MES-SA. In contrast,Taxol exhibited a higher IC₅₀ for the for multidrug resistant cell lineMES/SA-DX5 than for non-multidrug resistant lines HL 60 and MES-SA.Compounds 3 and 64 exhibited much greater activity than Taxol againstmultidrug resistant cell line MES/SA-DX. TABLE 2 Comp. 3 Comp. 64 TaxolCell Line Cell Type IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM HL60 Leukemia 0.4740.025 0.005 MES-SA Uterine 0.100 0.042 0.005 Carcinoma MES/DX5 MDR-10.080 0.033 10

Example 3 Cell Cycle Analysis

MDA-435 cells are cultured in 6-well plates at 1×10⁶ cells/well and areuntreated (negative control), treated with Taxol (positive control), ortreated with a compound of the invention at 37° C. for 20 h. The cellsare detached with 1× trypsin and washed one time with PBS. Cycle TESTPLUS kit (BD PharMingen, Cat # 340242) is used to stain the cells. Cellcycle is analyzed with FACScomp program (BS PharMingen).

Example 4 Inhibition of Tubulin Polymerization by Compounds of theInvention Material and Methods

Wild-type Chinese Hamster Ovary cells (WT CHO) cells are maintained inHam's F-12 medium supplemented with 10% fetal bovine serum (FBS;HyClone, Logan, Utah). Cells of low density (˜20%) growing on 2-wellchambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific)are transfected with a mammalian expression vector encodingα-tubulin-YFP (Clontech, Palo Alto, Calif.) with the use of FuGENE 6(Roche Molecular Biochemicals, Indianapolis, Ind.), according to themanufacturer's instructions. Twenty-four hours after transfection, thecells are cultured in 400 μg/ml G418 (Invitrogen, Carlsbad,Calif.)-containing selection medium for 2 weeks. Living cells areexamined using a fluorescent microscope for α-tubulin-YFP expression.Cells in single colonies containing microtubules labeled withα-tubulin-YFP are lifted and expanded in G418-containing medium.Expression of α-tubulin-YFP is confirmed by the presence of thetubulin-YFP labeled microtubule pattern identical to immunostainedmicrotubule pattern of non-transfected cells, as well as by subjectingthe cells to Western blot analysis using an anti-GFP antibody (RocheMolecular Biochemicals, Basel, Switzerland) and confirming the correctmass of the α-tubulin-YFP chimeric protein. Expressed tubulin-YFP isdetected as a single band in Western blots. The tubulin-YFP expressingcell lines (referred as CHO-α-tubulin-YFP cells) are used in the studiesdescribed below. Similar methods are used to generate MCF-7 cell linesstably expressing α-tubulin-YFP (referred as MCF7-α-tubulin-YFP cells).

CHO-α-tubulin-YFP or MCF7-α-tubulin-YFP cells is cultured in 2-wellchambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific)for 24 hours before treatment with a compound of the invention. Forcomparison of the effects of treatment on α-tubulin-YFP labeledmicrotubules with the compounds of the invention, CHO-α-tubulin-YFP orMCF7-a-tubulin-YFP cells are treated with the α compound of theinvention, Taxol or equivalent concentrations of DMSO-containing mediafor various time periods before imaging. Tubulin-YFP fluorescence inliving cells or fixed cells is captured using a standard filter for FITCand objectives of 20× or 60× magnification on a Nikon TE300 microscopewith a Leica DC50 color digital camera (Leica, Bannockburn, Ill.) or aCoolSnap HQ monochrome CCD camera (Photonetrics, Tucson, Ariz.). TheLeica DC50 and CoolSnapHQ cameras are controlled with Leica DC50software and MetaVue/MetaMorph software, respectively (Universal ImagingCorp, Downingtown, Pa.). Inspection of the cells shows a typicalmicrotubule network in cells treated with DMSO alone, whereasmicrotubule bundle formation can be seen with Taxol, and a dispersepattern of cytoplasmic tubulin-YFP is expected with compounds of theinvention indicating microtubule depolymerization.

Example 5 Microtubule Disruption in Cells Resistant to theDepolymerization Effects of Colchicine and Vincristine

The effects of compounds of the invention on microtubules can be studiedin CV-1 cells. The microtubules of CV-1 cells are known to be resistantto the depolymerizing effects of colchicine and vincristine. CV-1 cellsare treated with 500 nM of a compound of the invention, vincristine, orcoichicines, and their microtubules are examined at 24, 48 and 72 hr(FIGS. 8, 9 and 10). Cells are then fixed and stained to examinemicrotubule structure. In cells treated with compounds of the invention,microtubule structures are expected to be diminished compared tountreated cells. Disorganized but clear microtubule structures aretypically found in cells treated with either vincristine or colchines.

Example 6 Anti-Tumor Activity Against Human Tumor Cells Line in NudeMouse Xenograft Models

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), is obtained from the American TypeCulture Collection (ATCC; Manassas, Va., USA). The human tumor cellline, RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer. Res.45:3274-3281, 1985), is obtained from the Riken Cell Bank (RCB; Tsukuba,Ibaraki, Japan). The cell lines are cultured in growth media preparedfrom 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media1640, 10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that are cryopreserved in liquid nitrogenare rapidly thawed at 37° C. and transferred to a 175 cm² tissue cultureflask containing 50 ml of growth media and then incubated at 37° C. in a5% CO₂ incubator. The growth media is replaced every 2-3 days until theflask becomes 90% confluent, typically in 5-7 days. To passage andexpand the cell line, a 90% confluent flask is washed with 10 mL of roomtemperature phosphate buffered saline (PBS) and the cells aredisassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) and incubatedat 37° C. until the cells detach from the surface of the flask. Toinactivate the trypsin, 5 mL of growth media is added and then thecontents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10(6) cells per flask were seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells are obtained for implantationinto mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 7 and 19 weeksof age at implantation. To implant MDA-MB-435S tumor cells into nudemice, the cells are trypsinized as above, washed in PBS and resusupendedat a concentration of 50×10(6) cells/mL in PBS. Using a 27 gauge needleand 1 cc syringe, 0.1 mL of the cell suspension is injected into thecorpus adiposum of nude mice. The corpus adiposum is a fat body locatedin the ventral abdominal vicera in the right quadrant of the abdomen atthe juncture of the os coxae (pelvic bone) and the os femoris-(femur).To implant RERF-LC-AI tumor cells into nude mice, the cells aretrypsinized as above, washed in PBS and resuspended at a concentrationof 50×10(6) cells/mL in 50% non-supplemented RPMI Media 1640 and 50%Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford,Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mL of thecell suspension is injected subcutaneously into the flank of nude mice.

Tumors are then permitted to develop in vivo until they reachapproximately 100-200 mm³ in volume, which typically requires 2-3 weeksfollowing implantation. Tumor volumes (V) are calculated by calipermeasurement of the width (W), length (L) and thickness (T) of tumorsusing the following formula: V=0.5326×(L×W×T). Animals are randomizedinto treatment groups so that the average tumor volumes of each groupare similar at the start of dosing.

Stock solutions of test articles are prepared by dissolving theappropriate amounts of each compound in dimethyl sulfoxide (DMSO) bysonication in an ultrasonic water bath. Stock solutions are prepared atthe start of the study, stored at −20° C. and diluted fresh each day fordosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Ill.,USA) is also prepared by first heating 100% Cremophore RH40 at 50-60° C.until liquefied and clear, diluting 1:5 with 100% D5W, reheating againuntil clear and then mixing well. This solution is stored at roomtemperature for up to 3 months prior to use. To prepare formulations fordaily dosing, DMSO stock solutions are diluted 1:10 with 20% CremophoreRH40. The final formulation for dosing contains 10% DMSO, 18% CremophoreRH40, 3.6% dextrose, 68.4% water and the appropriate amount of testarticle (compound of the invention or paclitaxel). Animals areintravenously (i.v.) injected with this solution at 10 ml per kg bodyweight on a schedule of 3 days per week (Monday, Wednesday, Friday, withno dosing on Saturday and Sunday) for a total of 9-10 doses.

Treatment with compounds of the invention at, for example, 6.25, 12.5,and 25 mg/kg body weight are expected to decrease the growth rate and/orcause tumor regression of MDA-MB-435S melanoma cells or of RERF-LC-AIlung tumor cells in nude mice. Treatment with 7.5 mg/kg of paclitaxeltypically results in decreased tumor growth compared to animals treatedwith vehicle alone.

Example 7 Necrosis in a nude Mouse Tumor Model

Mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), are obtainedfrom the American Type Culture Collection (ATCC; Manassas, Va., USA).The cell line is cultured in growth media prepared from 50% Dulbecco'sModified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetalbovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 ml of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detached from the surface of theflask. To inactivate the trypsin, 5 ml of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 ml ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10(6) cells per flask are seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells are obtained for implantationinto mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resusupended at aconcentration of 10×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

Tumors are then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically required 1 week followingimplantation. Animals with oblong, very small or large tumors arediscarded, and only animals carrying tumors that display consistentgrowth rates are selected for studies. Tumor volumes (V) are calculatedby caliper measurement of the width (W), length (L) and thickness (T) oftumors using the following formula: V=0.5236×(L×W×T). Animals arerandomized into treatment groups so that each group has median tumorvolumes of ˜100 mm³ at the start of dosing.

To formulate compounds of the invention in DRD, a stock solution of thetest article is prepared by dissolving an appropriate amount of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) isalso prepared by first heating 100% Cremophore RH40 at 50-60° C. untilliquefied and clear, diluting 1:5 with 100% D5W, reheating again untilclear and then mixing well. This solution is stored at room temperaturefor up to 3 months prior to use. To prepare a DRD formulation fordosing, the DMSO stock solution is diluted 1:10 with 20% CremophoreRH40. The final DRD formulation for dosing contains 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article.

Tumor-bearing animals are given a single intravenous (i.v.) bolusinjections of either DRD vehicle or a compound of the inventionformulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr afterdrug treatment, tumors are excised, cut in half and fixed overnight in10% neutral-buffered formalin. Each tumor is embedded in paraffin withthe cut surfaces placed downwards in the block, and rough cut until acomplete section is obtained. From each tumor, 5 μM serial sections areprepared and stained with hematoxylin and eosin. Slides are evaluatedmanually using light microscopy with a 10×10 square gridded reticle. Thepercentage of necrosis in a tumor is quantified at 200× magnification byscoring the total number of grid squares containing necrosis and thetotal number of grid squares containing viable tumor cells.

It is expected that compounds of the invention will rapidly increasecell necrosis after injection (e.g. single bolus injection of 25 mg/kgbody weight) relative to baseline necrosis observed in vehicle treatedtumors, as would be expected for a vascular targeting mechanism ofaction. Such rapid onset of necrosis is consistent with there being aloss of blood flow to tumors resulting in hypoxia and tumor cell death.

Example 8 Vascular Disrupting Activities in a nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 mL of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice. Seven to eight week old, female Crl:CD-1-nuBR(nude) mice are obtained from Charles River Laboratories (Wilmington,Mass., USA). Animals are housed 4-5/cage in micro-isolators, with a 12hr/12 hr light/dark cycle, acclimated for at least 1 week prior to useand fed normal laboratory chow ad libitum. Studies are conducted onanimals between 8 and 10 weeks of age at implantation. To implant EMT6tumor cells into nude mice, the cells are trypsinized as above, washedin PBS and resusupended at a concentration of 10×10⁶ cells/mL in PBS.Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell suspensionis injected subcutaneously into the flank of each nude mouse.

For the Evans Blue dye assay, tumors are permitted to develop in vivountil the majority reach 40-90 mm³ in tumor volume (to minimize theextent of tumor necrosis), which typically require 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors are discarded and only animals carrying tumors that displayconsistent growth rates are selected for use. Tumor volumes (V) arecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals are randomized into treatment groups so that at the start ofdosing each group have median tumor volumes of −125 mm³ or ˜55 mm³ forthe Evans Blue dye assay.

To formulate compounds of the invention for dosing, the appropriateamount of compound is dissolved in 5% dextrose in water (D5W; AbbottLaboratories, North Chicago, Ill., USA). Vehicle-treated animals aredosed with D5W.

To conduct the Evans Blue dye assay, tumor-bearing animals are dosedwith vehicle or test article at 0 hr, and then i.v. injected with 100 μLof a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA)solution in 0.9% NaCl at +1 hr. Tumors are excised at +4 hr, weighed andthe tissue disassociated by incubation in 50 μL 1 N KOH at 60° C. for 16hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325 μLacetone are added, and the samples vigorously vortexed and thenmicrocentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant is then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that have not been injected with dye aresubtracted as background. OD₆₂₀ values are then normalized for tumorweight and dye uptake is calculated relative to vehicle-treated tumors.

To examine the vascular disrupting activity of a compound of theinvention, the Evans Blue dye assay is employed as a measurement oftumor blood volume (Graff et al., Eur J Cancer 36:1433-1440, 2000).Evans Blue dye makes a complex with serum albumin by electrostaticinteraction between the sulphonic acid group of the dye and the terminalcationic nitrogens of the lysine residues in albumin. The dye leaves thecirculation very slowly, principally by diffusion into extravasculartissues while still bound to albumin. Albumin-dye complex taken up bytumors is located in the extracellular space of non-necrotic tissue, andintracellular uptake and uptake in necrotic regions is negligible. Theamount of dye present in a tumor is a measurement of the tumor bloodvolume and microvessel permeability.

Compounds of the invention are expected to result in substantiallydecreased tumor dye uptake relative to vehicle-treated animals. Such adecrease in dye penetration into the tumor is consistent with therebeing a loss of blood flow to tumors due to blockage of tumorvasculature, consistent with a vascular disrupting mechanism of action.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

1. A method of inhibiting tubulin polymerization in a cell, comprisingcontacting the cell with an effective amount of a compound representedby formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.
 2. Themethod of claim 1, wherein the cell is in a subject and tubulinpolymerization is inhibited in the subject by administering to thesubject an effective amount of the compound.
 3. The method of claim 2,wherein the compound is represented by formula (V):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(i) or R_(j) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 4. A method of treating or preventing aproliferative disorder in a subject, comprising administering to thesubject an effective amount of a compound represented by formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.
 5. Themethod of claim 4, wherein the compound is represented by formula (V):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(i) or R_(j) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 6. The method of claim 2, wherein thecompound is represented by formula (IA):

wherein: R^(x) is (R^(aa))_(m), —R_(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(q)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; and q is 0or
 1. 7. The method of claim 6, wherein the compound is represented byformula (VA):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 8. The method of claim 4, wherein thecompound is represented by formula (IA):

wherein: R_(x) is (R^(aa))_(m), —R_(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or—(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, analkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, foreach occurrence, is independently —H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; and q is 0or
 1. 9. The method of claim 8, wherein the compound is represented byformula (VA):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 10. The method of claim 2, wherein thecompound is represented by formula (IB):

wherein: R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl; and R₇, for each occurrence, is independently —H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl.
 11. The method of claim 10, wherein thecompound is represented by formula (VB):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 12. The method of claim 4, wherein thecompound is represented by formula (IB):

wherein: R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl; and R₇, for each occurrence, is independently —H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl.
 13. The method of claim 12, wherein thecompound is represented by formula (VB):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 14. A method of blocking, occluding, orotherwise disrupting blood flow in neovasculature, comprising contactingthe neovasculature with an effective amount of a compound represented byformula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.
 15. Themethod of claim 14, wherein the neovasculature is in a subject and bloodflow in the neovasculature is blocked, occluded, or other otherwisedisrupted in the subject by administering to the subject an effectiveamount of the compound.
 16. The method of claim 15, wherein the compoundis represented by formula (V):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 17. The method of claim 15, wherein thecompound is represented by formula (IA):

wherein: R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or—(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, analkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, foreach occurrence, is independently —H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; and q is 0or
 1. 18. The method of claim 17, wherein the compound is represented byformula (VA):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 19. The method of claim 15, wherein thecompound is represented by formula (IB):

wherein: R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl; and R₇, for each occurrence, is independently —H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl.
 20. The method of claim 19, wherein thecompound is represented by formula (VB):

wherein: one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 21. A method of treating or preventingmacular degeneration in a subject, comprising administering to thesubject an effective amount of a compound represented by formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.
 22. Themethod of claim 21, wherein the compound is represented by formula (IA):

wherein: R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, C(O)YR^(z), —C(O)NH—R^(aa), or(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; and q is 0or
 1. 23. The method of claim 21, wherein the compound is represented byformula (IB):

wherein: R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl; and R₇, for each occurrence, is independently —H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl.
 24. A compound represented by formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR₂ is an optionally substituted aryl or an optionally substitutedheteroaryl, provided that R₂ is not an unsubstituted phenyl.
 25. Thecompound of claim 24, wherein the compound is represented by formula(V):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein: one of R_(i) or R_(j) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 26. The compound of claim 25, wherein X₁and X₂ are CH.
 27. The compound of claim 26, wherein R₁₂, R₁₃ and R₁₄are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl.
 28. The compound of claim 27, wherein R₁₂, R₁₃ and R₁₄ aremethoxy.
 29. The compound of claim 27, wherein R₂ is a substitutedphenyl.
 30. The compound of claim 27, wherein R₂ is an optionallysubstituted naphthalenyl, an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, anoptionally substituted pyridinyl-phenyl, an optionally substitutedpyridinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted oxazolyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, or an optionally substituted benzofuranyl. 31.The compound of claim 24, wherein the compound is represented by formula(VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(k) or R_(l) is —H and the other isrepresented by the following formula:

the dashed line indicates that the bond is a single bond or a doublebond; X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S; X₅and X₆ are each, independently, CR₂₉ or N; R₁₅ is H, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for eachoccurrence, are, independently, —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₆ is H, an alkyl, a cycloalkyl, anaralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₂₉, foreach occurrence, is independently, H or a substituent; and p is 1 or 2.32. The compound of claim 31, wherein R₂ is a substituted phenyl. 33.The compound of claim 31, wherein: R₁₅ is H, alkoxy, halo, alkyl,haloalkyl, haloalkoxy, nitro, cyano, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄,—OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆,guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈,—S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇,—OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; and R₂₉, for each occurrence, isindependently, H, alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro,cyano, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆,—NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)O R₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂.
 34. Thecompound of claim 31, wherein R₂ is an optionally substitutednaphthalenyl, an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl,an optionally substituted biphenyl, an optionally substitutedpyridinyl-phenyl, an optionally substituted pyridinyl, an optionallysubstituted quinolinyl, an optionally substituted isoquinolinyl, anoptionally substituted 1H-indolyl, an optionally substituted oxazolyl,an optionally substituted benzo[1,3]dioxolyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, or an optionallysubstituted benzofuranyl.
 35. The compound of claim 24, wherein thecompound is represented by formula (VII):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein: one of R_(m) or R_(n) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₂ is an optionallysubstituted aryl or an optionally substituted heteroaryl; R₁₈ and R₁₉are each, independently, halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, cyano,nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₀ is an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for eachoccurrence, are, independently, —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; and p is 1 or
 2. 36. Thecompound of claim 35, wherein R₂ is a substituted phenyl.
 37. Thecompound of claim 35, wherein: R₁₈ and R₁₉ are each, independently, analkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₂₀is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester.
 38. The compoundof claim 35, wherein X₁ and X₂ are CH.
 39. The compound of claim 35,wherein R₂ is an optionally substituted naphthalenyl, an optionallysubstituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substitutedbiphenyl, an optionally substituted pyridinyl-phenyl, an optionallysubstituted pyridinyl, an optionally substituted quinolinyl, anoptionally substituted isoquinolinyl, an optionally substituted1H-indolyl, an optionally substituted oxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted pyridazinyl,an optionally substituted pyrimidinyl, or an optionally substitutedbenzofuranyl.
 40. The compound of claim 24, wherein the compound isrepresented by formula (VII):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein: one of R_(o) or R_(p) is —H and the other isrepresented by the following

X₁ and X₂ are each, independently, CH or N; R₂ is an optionallysubstituted aryl or an optionally substituted heteroaryl; R₂₁ is halo,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₂ and R₂₃ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence,are, independently, —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; R₁₇, for each occurrence, is independently, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; and p is 1 or
 2. 41. The compound of claim 40, wherein R₂is a substituted phenyl.
 42. The compound of claim 40, wherein: R₂₂ andR₂₃ are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl; and R₂₁ is an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester. 43.The compound of claim 40, wherein X₁ and X₂ are CH.
 44. The compound ofclaim 40, wherein R₂ is an optionally substituted naphthalenyl, anoptionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionallysubstituted biphenyl, an optionally substituted pyridinyl-phenyl, anoptionally substituted pyridinyl, an optionally substituted quinolinyl,an optionally substituted isoquinolinyl, an optionally substituted1H-indolyl, an optionally substituted oxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted pyridazinyl,an optionally substituted pyrimidinyl, or an optionally substitutedbenzofuranyl.
 45. A compound represented by formula (IA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or(R^(aa))_(q)C(O)(Y₁); R^(y) is —H or lower alkyl; R^(w) is —H, an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; R₇, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R^(aa)is an amino acid residue or an amino acid residue analog; Y is CH₂, O,or NH; R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁; Alk is an optionallysubstituted alkylene; Het is an optionally substituted heteroalkyl; Y₁is a water soluble polymer with a molecular weight less than 60,000daltons; n is 1, 2, 3, or 4; m is an integer from 1 to 10; and q is 0or
 1. 46. The compound of claim 45, wherein the compound is representedby formula (VA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(i) or R_(j) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 47. The compound of claim 46, wherein X₁and X₂ are CH.
 48. The compound of claim 47, wherein R₁₂, R₁₃ and R₁₄are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl.
 49. The compound of claim 48, wherein R₁₂, R₁₃ and R₁₄ aremethoxy.
 50. The compound of claim 48, wherein R^(y) is —H.
 51. Thecompound of claim 48, wherein R^(w) is alkoxy.
 52. The compound of claim51, wherein R^(w) is methoxy.
 53. The compound of claim 48, whereinR^(x) is R^(aa), —C(O)YR^(z), or —C(O)NH—R^(aa).
 54. The compound ofclaim 53, wherein R^(x) is —C(O)YR^(z).
 55. The compound of claim 54,wherein R^(z) is Y₁.
 56. The compound of claim 53, wherein R^(x) isR^(aa).
 57. The compound of claim 56, wherein Y₁ is PEG, HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-OH.
 58. The compound of claim 45,wherein X₁ and X₂ are CH; R₁₂, R₁₃ and R₁₄ are methoxy; R_(j) is —H;R^(w) is methoxy R^(x) is R_(aa); and R^(y) is —H.
 59. The compound ofclaim 45, wherein the compound is represented by formula (VIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(k) or R_(l) is —H and the other isrepresented by the following formula:

the dashed line indicates that the bond is a single bond or a doublebond; X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S; X₅and X₆ are each, independently, CR₂₉ or N; R₁₅ is H, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₆ is H, an alkyl, a cycloalkyl, anaralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₂₉, foreach occurrence, is independently, H or a substituent; and p is 1 or 2.60. The compound of claim 45, wherein the compound is represented byformula (VIIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(m) or R_(n) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₈ and R₁₉, are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₀ is an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, cyano,nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₁₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; and p is 1 or
 2. 61. Thecompound of claim 60, wherein X₁ and X₂ are CH.
 62. The compound ofclaim 45, wherein the compound is represented by formula (VIIIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(o) or R_(p) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₂₂ and R₂₃, are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₁ is halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; p is 1 or
 2. 63. The compound ofclaim 62, wherein X₁ and X₂ are CH.
 64. A compound represented byformula (IB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(a) or R_(b) is —H and the other is anoptionally substituted aryl or an optionally substituted heteroaryl; andR^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, analkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₇,for each occurrence, is independently —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl.
 65. Thecompound of claim 64, wherein the compound is represented by formula

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(i) or R_(j) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₂, R₁₃ and R₁₄ are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for each occurrence, isindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; R₁₀ and R₁₁, for eachoccurrence, are independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀and R₁₁, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl; and p is 1 or
 2. 66. The compound of claim 65, wherein X₁and X₂ are CH.
 67. The compound of claim 66, wherein R₁₂, R₁₃ and R₁₄are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, ahaloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, orhydroxyl.
 68. The compound of claim 67, wherein R₁₂, R₁₃ and R₁₄ aremethoxy.
 69. The compound of claim 68, wherein R_(w) is alkoxy.
 70. Thecompound of claim 69, wherein R_(w) is methoxy.
 71. The compound ofclaim 64, wherein the compound is represented by structural formula(VIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(k) or R_(l) is —H and the other isrepresented by the following formula:

the dashed line indicates that the bond is a single bond or a doublebond; X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S; X₅and X₆ are each, independently, CR₂₉ or N; R₁₅ is H, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₆ is H, an alkyl, a cycloalkyl, anaralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₂₉, foreach occurrence, is independently, H or a substituent; and p is 1 or 2.72. The compound of claim 64, wherein the compound is represented bystructural formula (VIIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(m) or R_(n) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₁₈ and R₁₉, are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₀ is an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, cyano,nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₁₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; and p is 1 or 2;
 73. Thecompound of claim 72, wherein X₁ and X₂ are CH.
 74. The compound ofclaim 64, wherein the compound is represented by structural formula(VIIIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(o) or R_(p) is —H and the other isrepresented by the following formula:

X₁ and X₂ are each, independently, CH or N; R₂₂ and R₂₃, are each,independently, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₁ is halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl,—OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₈, for eachoccurrence, is independently —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; and p is 1 or
 2. 75. Thecompound of claim 74, wherein X₁ and X₂ are CH.
 76. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and acompound of any one of claims 24, 45, or
 64. 77. The pharmaceuticalcomposition of claim 76, further comprising one or more additionaltherapeutic agents.